Bicyclic heterocyclic substituted phenyl oxazolidinone antibacterials, and related compositions and methods

ABSTRACT

Bicyclic heterocyclic substituted phenyl oxazolidinone compounds of the formula:  
                 
 
     wherein Y is a radical of Formulae II or III:  
                 
 
     in which the substituents have the meaning indicated in the description. These compounds are useful as antibacterial agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part to U.S. applicationSer. No. 09/621,814 filed on Jul. 21, 2000.

FIELD OF THE INVENTION

[0002] The present invention relates to the field of phenyloxazolidinone compounds having antibacterial activity againstGram-positive and Gram-negative bacteria, pharmaceutical compositionscontaining the compounds, and methods of treating bacterial infectionswith the compounds.

BACKGROUND OF THE INVENTION

[0003] Oxazolidinones have been identified, within the last twentyyears, as a new class of antibacterials which are active againstnumerous multidrug-resistant gram positive organisms. Particularlyproblematic pathogens include methicillin-resistant Staphylococcusaureus (MRSA), glycopeptide-intermediate resistant Staphylococcus aureus(GISA), vancomycin-resistant enterocci (VRE) and penicillin- andcephalosporin-resistant Streptococcus pneumoniae. As a class,oxazolidinones exhibit a unique mechanism of action. Studies have shownthat these compounds selectively bind to the 50S ribosomal subunit andinhibit bacterial translation at the initiation phase of proteinsynthesis. Exemplary members of oxazolidinones are linezolid (see WO95/07271) and eperezolid.

[0004] U.S. Pat. No. 5,792,765 to Riedl et al. discloses a series ofsubstituted oxazolidinones (cyanoguanidine, cyanoamidines, and amidines)useful as antibacterial medicaments.

[0005] U.S. Pat. No. 5,910,504 to Hutchinson discloses a series ofhetero-aromatic ring substituted phenyl oxazolidinones, includingindolyl substituted compounds useful as antibacterial agents.

[0006] WO 98/54161 (Hester et al.) discloses amides, thioamides, ureas,and thioureas which are antibacterial agents.

[0007] WO 95/07271 (Barbachyn et al.) discloses oxazine and thiazineoxazolidinone derivatives such as linezolid and its analogs which areuseful antimicrobial agents, effective against a number of human andveterinary pathogens, including gram-positive aerobic bacteria such asmultiple-resistant staphylococci, streptococci and enterococci as wellas anaerobic organisms such as Bacteroides spp. and Clostridia spp.species, and acid-fast organisms such as Mycobacterium tuberculosis,Mycobacterium avium and Mycobacterium spp.

[0008] WO 93/09103 (Barbachyn et al.) discloses substituted aryl- andheteroarylphenyloxazolidinones which are useful as antibacterial agents.

SUMMARY OF THE INVENTION

[0009] The invention provides phenyl oxazolidinone compounds of FormulaI:

[0010] wherein:

[0011] R is selected from the group consisting of OH, O-Aryl,O-Heteroaryl, N₃, OR′, OSO₂R″, —NR′″R″″, or

[0012]  wherein:

[0013] (i) R′ is straight-chain or branched acyl having up to 6 carbonatoms or benzyl;

[0014] (ii) R″ is straight-chain or branched alkyl, having up to 5carbon atoms, phenyl or tolyl; and

[0015] (iii) R′″ and R″″ are independently selected from the groupconsisting of H, cycloalkyl having 3 to 6 carbon atoms, phenyl ortert-butoxycarbonyl, fluorenyloxycarbonyl, benzyloxycarbonyl,straight-chain or branched alkyl having up to 6 carbon atoms which isoptionally substituted by cyano or alkoxycarbonyl having up to 4 carbonatoms, —CO₂—R₁, —CO—R₁, —CS—R₁, and —SO₂—R₄, in which

[0016] R₁ is selected from the group consisting of H, cycloalkyl having3 to 6 carbon atoms, trifluoromethyl or phenyl, benzyl or acyl having upto 5 carbon atoms, straight-chain or branched alkyl having up to 6carbon atoms, said alkyl optionally substituted by straight-chain orbranched alkoxycarbonyl having up to 5 carbon atoms, OH, cyano, up to 3halogen atoms, and —NR₅ R₆ in which R₅ and R₆ are identical or differentand are selected from H, phenyl or straight-chain or branched alkylhaving up to 4 carbon atoms;

[0017] R₄ is selected from straight-chain or branched alkyl having up to4 carbon atoms or phenyl and;

[0018] R_(4a) is CN, COR_(4c), COOR_(4c), CONHR_(4c), CO—NR_(4c) R_(4d),SO₂R_(4c), or NO₂;

[0019] R_(4b) is H, alkyl, OR_(4c), SR_(4c), amino, NHR_(4c),NR_(4c),R_(4d);

[0020] R_(4c) and R_(4d) are independently selected from H, alkyl, aryl,or in the case of any NR_(4c)R_(4d) group R_(4c) and R_(4d) takentogether with the nitrogen atom to which they are attached form aunsubstituted or substituted pyrrolidinyl, piperidinyl or morpholinylgroup;

[0021] X is 0 to 4 members independently selected from the groupconsisting of halogen, OH, nitro, C₁₋₈ alkoxy, C₁₋₈ alkyl-amino,di(C₁₋₈-alkyl-)amino, carboxy, alkoxycarbonyl, C₁₋₈ alkyl-CO—O—, C₁₋₈alkyl-CO—NH—, carboxamide, CN, amine, C₃₋₆ cycloalkyl, C₁₋₈ alkyloptionally substituted with one or more members selected from the groupconsisting of F, Cl, OH; and

[0022] Y is a radical of Formulae II or III:

[0023]  wherein

[0024] R₅, R₆, R₇, and R₈ are each independently H, alkyl, CN, nitro,C₁₋₈ alkyl, halo-C₁₋₈-alkyl, formyl, carboxy, alkoxycarbonyl,carboxamide, or R₅ and R₆ and/or R₇ and R₈ together form an oxo group;

[0025] R₉, and R₁₀ are each independently H, halogen, alkyl, OH, CN,nitro, C₁₋₈ alkyl, halo-C₁₋₈-alkyl, C₁₋₈ alkoxyl, amino,C₁₋₈-alkyl-amino, di(C₁₋₈-alkyl-)amino, formyl, carboxy, alkoxycarbonyl,C₁₋₈-alkyl- CO—O—, C₁₋₈-alkyl- CO—NH—, carboxamide, or amine;

[0026]  is a fused phenyl ring or a five- or six-membered heteroaromaticring having one to four members selected from the group consisting of S,O, and N;

[0027] Z is halogen, alkyl, substituted-alkyl, aryl, substituted-aryl,heteroaryl, substituted-heteroaryl, CN, CHO, COalkyl, amino, alkoxy,HNCO—(C₁-C₈alkyl), allyl, propargyl, allenyl, or N-alkylthiocarbamoyl;and

[0028] m is 0 or 1,

[0029] and the pharmaceutically acceptable salts and esters thereof.

[0030] Compounds of the above formula are useful as antibacterial agentsfor the treatment of bacterial infections in humans and animals.

[0031] The present invention is also directed to a method of treating asubject having a condition caused by or contributed to by bacterialinfection, which comprises administering to said mammal atherapeutically effective amount of the compound of Formula I.

[0032] The present invention is further directed to a method ofpreventing a subject from suffering from a condition caused by orcontributed to by bacterial infection, which comprises administering tothe subject a prophylactically effective dose of the pharmaceuticalcomposition of a compound of Formula I.

[0033] Other objects and advantages will become apparent to thoseskilled in the art from a review of the ensuing specification.

DETAILED DESCRIPTION

[0034] Relative to the above description of the phenyl oxazolidinonecompounds of the present invention, the following definitions apply.

[0035] Unless specified otherwise, the terms “alkyl”, “alkenyl”, and“alkynyl” may be straight or branched groups with 1-8 carbon atoms.

[0036] “Substituted alkyl” may be a straight or branched-chain moietywith 1-8 carbon atoms having one or more substituents selected from thegroup consisting of amino, dialkylamino, cycloalkyl, hydroxy, oxo,alkoxycarbonyl, benzyloxy, arylthio, alkylthio, hydroxyalkylthio,alkylsulfinyl, alkylsulfonyl, carboxy, phosphonooxy,dialkylphosphonooxy, dibenzylphosphonooxy, cyano, halo, trialkylsilyl,dialkylphenylsilyl, aryl, heteroaryl, heterocyclo,heterocyclomethylbenzoyloxy, dialkylaminomethylbenzoyloxy,dialkylaminoalkylcarbonyloxy, benzyloxycarbonylaminoalkylcarbonyloxy,and aminoalkylcarbonyloxy.

[0037] “Acyl” means an organic radical having the designated number ofcarbon atoms, derived from an organic acid by the removal of a hydroxylgroup having the formula RCO, as in the case of acetyl where R is CH₃.

[0038] “Aryl” is an unsubstituted carbocyclic aromatic group including,but not limited to, phenyl, 1- or 2-naphthyl and the like. “Heteroaryl”refers to a cyclic aromatic radical having from five to ten atoms in thering; where one to three ring atoms are independent heteroatoms such asS, O, and N, and the remaining ring atoms are carbon, for example, apyridinyl, pyrazinyl, pyrimidinyl, pyrroyl, pyrazolyl, imidazolyl,thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl,furanyl, quinolinyl, or isoquinolinyl, radical and the like.

[0039] “Substituted aryl” or “substituted heteroaryl” refers to an arylor heteroaryl substituted by independent replacement of 1-3 of thehydrogen atoms thereon with halogen, OH, CN, mercapto, nitro,C₁₋₈-alkyl, halo-C₁₋₈-alkyl, C₁₋₈-alkoxy, thio-C₁₋₈-alkyl, amino,C₁₋₈-alkyl-amine, di(C₁-C₈-alkyl-)amino, formyl, carboxy,alkoxycarbonyl, C₁₋₈-alkyl- CO—O—, C₁₋₈-alkyl- CO—NH—, or carboxamide.Further, substituted-heteroaryl may be substituted with a mono-oxo togive, for example, a 4-oxo-1-H-quinoline. Substituted-heteroaryl mayalso be substituted with a substituted-aryl or a secondsubstituted-heteroaryl to give, for example, a 4-phenyl-imidazol-1-yl ora 3-pyridinyl-imidazol-1-yl, and the like.

[0040] The terms “heterocycle,” “heterocyclic,” and “heterocyclo” referto an optionally substituted, fully saturated, partially saturated, ornon-aromatic cyclic group which is, for example, a 3- to 7-memberedmonocyclic, 7- to 11-membered bicyclic, or 10- to 15-membered tricyclicring system, which has at least one heteroatom in at least one carbonatom containing ring. Each ring of the heterocyclic group containing aheteroatom may have 1, 2, or 3 heteroatoms selected from nitrogen atoms,oxygen atoms, and sulfur atoms, where the nitrogen and sulfurheteroatoms may also optionally be oxidized. The nitrogen atoms mayoptionally be quaternized. The heterocyclic group may be attached at anyheteroatom or carbon atom.

[0041] The term “halo” or “halogen” means fluoro, chloro, bromo andiodo. (mono-, di-, tri-, and per-) halo-alkyl is an alkyl radicalsubstituted by independent replacement of the hydrogen atoms thereonwith halogen. P denotes phosphorus.

[0042] The compounds of the instant invention are asymmetric in theoxazolidinone ring at the 5- position and thus exist as opticalantipodes. As such, all possible optical antipodes, enantiomers ordiastereomers resulting from additional asymmetric centers that mayexist in optical antipodes, racemates and racemic mixtures thereof arealso part of this invention. The antipodes can be separated by methodsknown to those skilled in the art such as, for example, fractionalrecrystallization of diastereomeric salts of enantiomerically pureacids. Alternatively, the antipodes can be separated by chromatographyon a Pirkle column.

[0043] The phrase “pharmaceutically acceptable salts” denotes salts ofthe free base which possess the desired pharmacological activity of thefree base and which are neither biologically nor otherwise undesirable.These salts may be derived from inorganic or organic acids. Examples ofinorganic acids are hydrochloric acid, nitric acid, hydrobromic acid,sulfuric acid, or phosphoric acid. Examples of organic acids are aceticacid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonicacid, succinic acid, malic acid, maleic acid, fumaric acid, tartaricacid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,methyl sulfonic acid, salicyclic acid and the like. Suitable salts arefurthermore those of inorganic or organic bases, such as KOH, NaOH,Ca(OH)₂, Al(OH)₃, piperidine, morpholine, ethylamine, triethylamine andthe like.

[0044] Also included within the scope of the invention are the hydratedforms of the compounds which contain various amounts of water, forinstance, the hydrate, hemihydrate and sesquihydrate forms.

[0045] The term “subject” includes, without limitation, any animal orartificially modified animal. In the preferred embodiment, the subjectis a human.

[0046] The term “drug-resistant” or “drug-resistance” refers to thecharacteristics of a microbe to survive in presence of a currentlyavailable antimicrobial agent at its routine, effective concentration.

[0047] The compounds of the present invention possess antibacterialactivity against Gram-positive and certain Gram-negative bacteria. Theyare useful as antibacterial agents for the treatment of bacterialinfections in humans and animals. Particularly, these compounds haveantimicrobial activity against S. aureus, S. epidermidis, S. pneumoniae,E. faecalis, E. faecium, Moraxella catarrhalis, and H. influenzae. Moreparticularly, these compounds are useful against resistant bacteria suchas MRSA and GISA, and have a low susceptibility to acquired resistancemechanisms.

[0048] Compounds of Formula I which are preferred for such purposes arethose in which R is any of the following:

[0049] In addition Compounds of Formula I which are preferred for suchpurposes are those in which Y is any of the following:

[0050] In addition, Compounds of Formula I which are preferred for suchpurposes or those in which Z is any of the following: propargyl, allyl,allenyl, N-alkylthiocarbamoyl, alkyl, heteroaryl,substituted-heteroaryl, or a substituted alkyl having one or moresubstituents selected form the group consisting of amino, dialkylamino,cycloalkyl, hydroxy, oxo, alkoxycarbonyl, benzyloxy, arylthio,alkylthio, hydroxyalkylthio, alkylsulfinyl, alkylsulfonyl, carboxy,phosphonooxy, dialkylphosphonooxy, dibenzylphosphonooxy, cyano, halo,trialkylsilyl, dialkylphenylsilyl, aryl, heteroaryl, heterocyclo,heterocyclomethylbenzoyloxy, dialkylaminomethylbenzoyloxy,dialkylaminoalkylcarbonyloxy, benzyloxycarbonylaminoalkylcarbonyloxy,and aminoalkylcarbonyloxy.

[0051] Particularly preferred Compounds of Formula I are those wherein Zis selected from the group consisting of propargyl, allyl, allenyl,N-alkylthiocarbamoyl, ethyl, isopropyl, t-butyl, 2-hydroxyethyl,3-hydroxypropyl, 2,2,2-trifluoroethyl, cyanomethyl, 2-cyanoethyl,cyclopropylmethyl, 2-oxopropyl, methylthiomethyl, 2-methylthioethyl,methylsulfonylmethyl, 2-methylsulfonylethyl, methylsulfinylmethyl,t-butoxycarbonylmethyl, 2-carboxyethyl, 2-(di-t-butylphosphonooxy)ethyl,2-(dibenzylphosphonooxy)ethyl, 2-phosphonooxyethyl, 2-aminoethyl,2-(diethylamino)ethyl, 2-(dimethylamino)ethyl, 2-(4-morpholinyl)ethyl,2-(4-thiomorpholinyl)ethyl, trimethylsilylmethyl,dimethylphenylsilylmethyl, benzyloxymethyl, benzyl, 5-tetrazolylmethyl,3-pyridylmethyl, 2-pyridylmethyl, 2-oxiranylmethyl,2-oxooxazolidin-5-ylmethyl, 2,3-dihydroxypropyl,2-hydroxy-3-(1-piperidinyl)propyl, 2-hydroxy-3-(4-morpholinyl)propyl,2-hydroxy-3-phenylthiopropyl, 2-hydroxy-3-ethylthiopropyl,2-hydroxy-3-(2-hydroxyethylthio)propyl,3-[4-(1,1-dioxothiomorpholinyl)]-2-hydroxypropyl,3-ethylsulfinyl-2-hydroxypropyl,2-[4-(4-morpholinylmethyl)benzoyloxy]ethyl,2-[4-(dimethylaminomethyl)benzoyloxy]ethyl,2-[4-(4-methyl-1-piperazinylmethyl)benzoyloxy]ethyl,2-(dimethylaminoacetoxy)ethyl,2-[2-(benzyloxycarbonylamino)-3-methylbutyryloxy]ethyl,2-(2-amino-3-methylbutyryloxy)ethyl, 2-pyridinyl, pyridazinyl, and2-pyrimidinyl.

[0052] Particular examples of the present invention include thefollowing compounds:

[0053]N-[[(5S)-3-[4-(1,3-Dihydro-2H-isoindol-2-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;

[0054]N-[[(5S)-3-[4-(1,3-Dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;

[0055]N-[[(5S)-3-[3-Fluoro-4-(5-oxido-2H-pyrrolo[3,4-c]pyridin-2-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;

[0056]N-[[(5S)-3-[4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;

[0057]N-[[(5S)-3-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;and

[0058](5R)-3-[4-(5,7-Dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenyl]-5-(hydroxymethyl)-2-oxazolidinone;

[0059]N-[[(5S)-3-[4-[2,6-dihydro-2-(2-hydroxyethyl)pyrrolo[3,4-c]pyrazol-5(4H)-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;

[0060]N-[[(5S)-3-[4-[2,6-dihydro-2-[(2R)-2,3-dihydroxypropyl]pyrrolo[3,4-c]pyrazol-5(4H)-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;

[0061]N-[[(5S)-3-[4-[2,6-dihydro-2-[(2S)-2,3-dihydroxypropyl]pyrrolo[3,4-c]pyrazol-5(4H)-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;

[0062]N-[[(5S)-3-[4-(2,6-dihydro-2-propargylpyrrolo[3,4-c]pyrazol-5(4H)-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;

[0063]N-[[(5S)-3-[4-(2,6-dihydro-2-cyanomethylpyrrolo[3,4-c]pyrazol-5(4H)-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;

[0064] The compounds of Formula I that are the subject of this inventionmay be prepared from readily available starting materials such asisoindole (Gawley et al., J. Org. Chem., 1988, 53:5381),6,7-dihydro-5H-pyrrolo[3,4-c]pyridine and6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (U.S. Pat. No. 5,371,090 toPetersen et al.) in accordance with synthetic methods well known in theart. Representative procedures are outlined in Scheme I-V:

[0065] In accordance with Scheme I, bicyclic heterocycles of generalformula IV are treated with a substituted nitrobenzene derivative (L isan appropriate leaving group such as a halogen oftrifluoromethanesulfonyloxy) in a suitable base and solvent, such asdiisopropylamine and ethyl acetate, to give the substituted nitrophenylcompound V.

[0066] The nitrobenzene derivative V is then reduced to the aniline byan appropriate reaction, for instance by treatment with SnCl₂ or bycatalytic hydrogenation in the presence of a suitable catalyst, such aspalladium on carbon. The aniline is then treated with benzyl or methylchloroformate and sodium bicarbonate to form the corresponding benzyl ormethyl carbamate derivative VI.

[0067] The Cbz aniline VI is then deprotonated with a lithium base suchas n-butyllithium and reacted with (R)-glycidyl butyrate to afford theoxazolidinone VII. The hydroxymethyl group can then be converted to anamide as shown in Scheme I by preparation of the mesylate, conversion toazide VII, and reduction to amine IX by an appropriate procedure such ashydrogenation. Alternatively displacement of a mesylate (Scheme II) orappropiate leaving group such as tosylate or chlorine with potassiumphthalimide and removal of the phthaloyl protecting group byhydrazinolysis would provide amine IX. The amine IX can be converted toamide X by an acylation reaction using techniques known in the art, suchas treatment with acetic anhydride in the presence of a base such aspyridine. Alternatively, amine IX can be converted to a carbamate XI bytreatment with methylchloroformate and pyridine, or reacted with asulfonyl chloride in an inert solvent in the presence of an organic baselike pyridine to form a sulfonamide XII

[0068] For the formation of oxazolidione in which R=O-Heteroaryl (XIII),the oxazolidinone carbinol VII can be converted to the correspondingmesylate or other appropriate leaving group and reacted with HO-Het (asuitible hydroxyl containing heterocycle), either in the presence ofbase or with HO-Het as a preformed alkoxide, in an appropriate solvent,for example DMF or acetonitrile (Scheme III). Alternatively, Mitsunobuconditions can be used to couple VII with HO-Heterocycle by treatingwith triphenylphosphine and diisopropyl azodicarboxylate (DIAD) in anappropriate solvent, such as THF, at a suitable temperature, preferablyroom temperature. Reaction conditions and leading references can befound in Gravestock et al, WO99/64416.

[0069] Furthermore, by treating VII with a suitable, non-nucleophilicbase, for example NaH, the displacement of a leaving group (LG), such aschlorine or bromine, can be effected from an appropriately reactiveaza-heterocycle (LG-Het)(Scheme III).

[0070] Compounds of structure XIV can be prepared as shown in Scheme IV.Amine IX can be converted to various functionalized amidines by reactionwith activated imines, where Q is a leaving group such as methylthio ormethoxy, in a suitable solvent, for example toluene or methanol, with orwithout a catalyst (such AgNO₃) present at a temperature range of 0-110°C.

[0071] In accordance with Scheme V pyrrolidinone XV (prepared as inWO96/13502) is first reacted with methoxy-bis(dimethylamine) or otheractivated dimethylformamide reagent and, second, heated in a suitablesolvent (for example DMF and benzene) with either substituted amidines,to form pyrrolopyrimidines oxazolidinones such as XVI, or substitutedhydrazines, to form pyrrolopyrazole oxazolidinones such as XVII.Formation of the—enamine, alkoxymethylene or alkoxycarbonyl derivativesof pyrrolidinone XV, according to Brighty et al in U.S. Pat. No.5,037,834A, would also allow access to these systems.

[0072] As shown in Scheme VI compounds with the structure XIX can beachieved by oxidation of the various compounds, XVIII, using anappropriate oxidant (for example manganese dioxide, peroxyacetic acid,DDQ or air) in a suitable solvent such as methylene chloride.

[0073] Oxo-derivatives of structure XXII in Scheme VII, (X=O, Y=H₂ orX=H₂, Y=O) can be constructed by reacting 1,2-aryl dicarboxaldehydes(where XXI, U=H) with aniline XX (prepared as in WO96/23788) in thepresence of acids, such as acetic acid, in a suitable solvent such asmethylene chloride. The di-oxo-derivatives (structure XXII where X=Y=O)are prepared from the reaction of aniline XX with selected 1,2-aryldicarbonyl reagents with a suitable leaving group (XXI where U=Cl, Br,etc).

[0074] Compounds of the structure XXIV and XVII can be prepared as shownin Scheme VII. Pyrazole XXIII can be converted to regioisomericalkylated pyrazoles by reaction with a base, such as potassiumtert-butoxide , sodium hydride, or cesium carbonate, and an alkylatingagent, such as an alkyl halide.

[0075] Pyrazole XXV can be further functionalized (Scheme IX) byconversion of the hydroxyl group to an appropriate leaving group, suchas mesylate or halide, and displacement with nucleophiles, such as anamine, thiol, etc to afford substituted pyrazoles such as XXVI where Xrepresents nitrogen, sulfur, etc.

[0076] Various derivatives [amino acid (XXVII), phosphate (XXVIII) andsubstituted benzoic acid (XXIX)] with greater aqueous solubility can beprepared as illustrated in Scheme X. Coupling of pyrazole XXV with anamino acid derivative can be accomplished using a coupling reagent,such, as EDCI and DMAP. Following coupling, the amino acid protectinggroups can be remove (if so desired) by standard literature methodsknown to those skilled in the art. Phosphate derivative XXVIII can beprepared by a three-step procedure via reaction of pyrazole XXV withdialkyl(dialkylamino)phosphite and tetrazole, oxidation of thephosphorous with meta-chloroperoxybenzoic acid and removal of tert-butylprotecting groups with acid, such as TFA in methylene chloride. Watersoluble benzoic acid derivative XXIX can be prepared by initial couplingof pyrazole XXV with 2-(chloromethyl)benzoyl chloride, utilizingtriethyl amine as base, and then displacement of the halide with anamine, such morpholine, dimethylamine and the like, employing sodiumiodide as a catalyst.

[0077] Substituted 2-hydroxy propyl pyrazoles can be prepared throughattack on the epoxide functionality of Compound XXX with variousnucleophiles, such an amine, thiol, etc. to provide pyrazoles such asXXXI where X represents nitrogen, sulfur, etc (Scheme XI). The sulfurcontaining analogs, represented by Compound XXXII where X represents aninert linking group (Scheme XII), can be further functionalized byreaction with oxidizing agent, such as meta-chloroperoxybenzoic acid ortetrabutylammonium oxone, to provide sulfoxide or sulfone analogs, suchas XXXIII.

[0078] Tetrazole XXXV can be prepared by reaction of nitrile XXXIV withazidotrimethylsilane and catalytic dibutyltinoxide provides tetrazole(Scheme XII).

[0079] Definitions

[0080] All temperatures are in degrees Centigrade

[0081] Brine refers to an saturated aqueous sodium chloride solution

[0082] DMF refers to N,N-dimethylformamide

[0083] THF refers to tetrahydrofuran

[0084] Cbz refers to carbobenzyloxy

[0085] n-BuLi refers to n-butyl lithium

[0086] MS refers to mass spectrometry expressed as m/e or mass/chargeunit

[0087] [M+H] refers to the positive ion of a parent plus a hydrogen atom

[0088] Ether refers to diethyl ether

[0089] RT refers to room temperature

[0090] Mp refers to melting point

[0091] CH₂Cl₂ refers to methylene chloride

[0092] NaOH refers to sodium hydroxide

[0093] MeOH refers to methanol

[0094] EtOAc refers to ethyl acetate

[0095] ppt refers to a precipitate

[0096] These compounds have antimicrobial activity against susceptibleand drug resistant bacterial pathogens such as S. aureus, S.epidermidis, S. pneumoniae, S. pyogenes, Enterococcus spp., Moraxellacatarrhalis and H. influenzae. These compounds are particularly usefulagainst drug resistant Gram-positive cocci such as methicillin-resistantS. aureus and vancomycin-resistant enterococci. These compounds areuseful in the treatment of community-acquired pneumonia, upper and lowerrespiratory tract infections, skin and soft tissue infections,hospital-acquired lung infections, bone and joint infections, and otherbacterial infections.

[0097] Minimal inhibitory concentration (MIC) has been an indicator ofin vitro antibacterial activity widely used in the art. The in vitroantimicrobial activity of the compounds was determined by themicrodilution broth method following the test method from the NationalCommittee for Laboratory Standards (NCCLS). This method is described inthe NCCLS Document M7-A4, Vol.17, No.2, “Methods for DilutionAntimicrobial Susceptibility Test for Bacteria that GrowAerobically—Fourth Edition”, which is incorporated herein by reference.

[0098] In this method two-fold serial dilutions of drug in cationadjusted Muller-Hinton broth are added to wells in microdilution trays.The test organisms are prepared by adjusting the turbidity of activelygrowing broth cultures so that the final concentration of test organismafter it is added to the wells is approximately 5×10⁴ CFU/well.

[0099] Following inoculation of the microdilution trays, the trays areincubated at 35° C. for 16-20 hours and then read. The MIC is the lowestconcentration of test compound that completely inhibits growth of thetest organism. The amount of growth in the wells containing the testcompound is compared with the amount of growth in the growth-controlwells (no test compound) used in each tray. As set forth in Table 1,some compounds of the present invention were tested against a variety ofpathogenic bacteria resulting in a range of activities, from 1 to ≧128μg/mL depending on the organism tested. S. aureus OC2878 is a MRSA andE. faecium OC3312 is a vancomycin resistant enterococcus. TABLE 1 MICValues of Some Compounds of Formula I MIC (mg/mL) in Test Strains S.aureus S. aureus E. faecium Compound No. OC4172 OC2878 OC3312 1 2 2 2 22 1 4 3 0.5 0.25 0.5 4 1 0.5 1 5 >32 >32 >32 6 64 32 32 7 >32 8 16 8 8 48 9 >32 >32 >32 10 >32 8 64 11 2 1 2 12 8 2 4 13 2 1 2 14 32 16 16 15 22 2 16 8 8 8 17 4 2 2 18 16 16 16 19 8 4 8 20 4 2 4 21 >64 >64 >64 22 22 2 23 8 8 8 24 8 8 8 25 64 >128 32 26 1 0.5 1 27 8 4 8 28 0.5 0.5 0.529 >32 8 16 30 >128 >128 >128 31 >16 >16 >16 32 4 2 2 33 32 32 32 34 8 24 35 0.5 0.25 2 36 1 0.5 1 37 1 1 0.5 38 2 2 1 39 1 2 1 40 1 1 1 41 2 22 42 2 2 2 43 1 1 1 44 1 1 1 45 4 4 4 46 4 4 8 47 32 16 32 48 8 8 8 4916 4 8 50 8 4 8 51 32 32 32 52 8 4 8 53 8 4 4 54 32 32 16 55 8 8 8 56 10.5 1 57 0.5 0.5 1 58 32 4 16 59 1 0.5 1 60 8 8 8 61 4 4 4 62 1 1 2 63 44 4 64 8 16 16 65 1 0.5 2 66 2 2 2 67 2 0.5 1 68 2 2 2 69 2 2 4 70 8 4 871 2 1 2 72 2 1 2 73 8 4 4 74 4 4 4 75 4 2 4 76 16 8 8 77 8 4 16 78 4 12 79 4 2 4 80 8 2 4 81 16 8 16 82 2 1 2 83 >16 16 16 84 128 8 32 85 4 44 86 4 4 4 87 >32 >32 >32 88 32 128 64 89 1 1 2 90 2 2 4 91 4 4 8 92 4 24 93 4 2 4 94 2 2 2 95 4 2 2 96 16 16 16 97 8 8 8 98 4 2 4 99 4 2 4 1008 4 8 101 4 4 4 102 8 8 4 103 32 16 32 104 16 16 16 105 4 4 8 106 16 816 107 4 2 4 108 2 1 2 109 2 2 2 110 4 2 4 111 16 8 16 112 4 4 8 113 3232 >32 114 64 64 64 115 32 16 32 116 8 8 4 117 16 8 8 118 4 4 4 119 1616 32 120 16 16 16

[0100] This invention further provides a method of treating bacterialinfections, or enhancing or potentiating the activity of otherantibacterial agents, in a subject having conditions caused by orcontributed to by bacterial infection, which comprises administering tothe animals a compound of the invention alone or in admixture withanother antibacterial agent in the form of a medicament according to theinvention. The terms of “treating” and “treatment” includeadministering, either simultaneously, separately or sequentially, apharmaceutically effective amount of a composition containing one ofmore of the compounds disclosed herein to a subject that desiresinhibition of bacterial growth. The pharmaceutically effective amount ofthe compound used to practice the present invention for treatment variesdepending on the manner of administration, the age, weight, and generalhealth of the subject treated, and ultimately will be decided byphysicians or veterinarins.

[0101] The compounds of the present invention may be administered to asubject such as a human by any route appropriate to the condition to betreated, suitable routes including oral, rectal, nasal, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural). The preferred route may vary with, for example, the conditionof the recipient as well as the ease of preparation and administration.

[0102] When the compounds are employed for the above utility, they maybe combined with one or more pharmaceutically acceptable carriers, e.g.,solvents, diluents, and the like, and may be administered orally in suchforms as tablets, capsules, dispersible powders, granules, orsuspensions containing for example, from about 0.5% to 5% of suspendingagent, syrups containing, for example, from about 10% to 50% of sugar,and elixirs containing, for example, from about 20% to 50% ethanol, andthe like, or parenterally in the form of sterile injectable solutions orsuspensions containing from about 0.5% to 5% suspending agent in anisotonic medium. These pharmaceutical preparations may contain, forexample, from about 0.5% up to about 90% of the active ingredient incombination with the carrier, more usually between 5% and 60% by weight.

[0103] Compositions for topical application may take the form ofliquids, creams or gels, containing a therapeutically effectiveconcentration of a compound of the invention admixed with adermatologically acceptable carrier.

[0104] In preparing the compositions in oral dosage form, any of theusual pharmaceutical media may be employed. Solid carriers includestarch, lactose, dicalcium phosphate, microcrystalline cellulose,sucrose and kaolin, while liquid carriers include sterile water,polyethylene glycols, non-ionic surfactants and edible oils such ascorn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvants customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

[0105] The preferred pharmaceutical compositions from the standpoint ofease of preparation and administration are solid compositions,particularly tablets and hard-filled or liquid-filled capsules. Oraladministration of the compounds is preferred. These active compounds mayalso be administered parenterally or intraperitoneally. Solutions orsuspensions of these active compounds as a freebase or pharmacologicalacceptable salt can be prepared in water suitably mixed with asurfactant such as hydroxypropyl-cellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols and mixtures thereofin oils. Under ordinary conditions of storage and use, thesepreparations may contain a preservative to prevent the growth ofmicroorganisms.

[0106] The pharmaceutical forms suitable for injectable use includesterile aqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0107] The effective dosage of active ingredient employed may varydepending on the particular compound employed, the mode ofadministration and the severity of the condition being treated. However,in general, satisfactory results are obtained when the compounds of theinvention are administered at a daily dosage of from about 0.1 mg/kg toabout 400 mg/kg of animal body weight, preferably given in divided dosestwo to four times a day, or in sustained release form. For most largemammals the total daily dosage is from about 0.07 g to 7.0 g, preferablyfrom about 100 mg to 1000 mg. Dosage forms suitable for internal usecomprise from about 100 mg to 500 mg of the active compound in intimateadmixture with a solid or liquid pharmaceutically acceptable carrier.This dosage regimen may be adjusted to provide the optimal therapeuticresponse. For example, several divided doses may be administered dailyor the dose may be proportionally reduced as indicated by the exigenciesof the therapeutic situation.

[0108] The production of the above-mentioned pharmaceutical compositionsand medicaments is carried out by any method known in the art, forexample, by mixing the active ingredients(s) with the diluent(s) to forma pharmaceutical composition (e.g. a granulate) and then forming thecomposition into the medicament (e.g. tablets).

[0109] The following examples describe in detail the chemical synthesisof representative compounds of the present invention. The procedures areillustrations, and the invention should not be construed as beinglimited by chemical reactions and conditions they express. No attempthas been made to optimize the yields obtained in these reactions, and itwould be obvious to one skilled in the art that variations in reactiontimes, temperatures, solvents, and/or reagents could increase theyields.

EXAMPLE 1(5R)-3-[4-(1,3-Dihydro-1-oxo-2H-isoindol-2-yl)-3-fluorophenyl]-5-(hydroxymethyl)-2-oxazolidinone

[0110]

[0111] Isoindoline was synthesized employing the method of R. E. Gawley,S. R. Chemburkar, A. L. Smith, T. V. Anklekar J. Org. Chem. 1988, 53,5381.

[0112] Step 1:

[0113] To 3,4-difluoronitrobenzene (3.02 mL, 27.3 mmols) in ethylacetate at rt was added diisopropylethylamine (5.03 mL, 28.9 mmols) andthen isoindoline (3.50 g, 29.4 mmols) and stirred overnight. A yellowprecipitate (ppt) formed and was collected on a filter, washed withwater and ether and dried in a vacuum oven (30° C.) to provide theproduct as a bright yellow solid (6.69 g, 95% yield). Mp=200-202° C. MS(M+1)=327 m/z.

[0114] Step 2:

[0115] To the above nitro compound (2.62 g, 10.2 mmols) in ethanol (100mL) was added SnCl₂ (9.84 g, 50.9 mmols) and was refluxed for 16 hrs.After cooling to rt the reaction mixture was added to 10% aq. NaOH (300mL) and extracted with CH₂Cl₂ (6×50 mL). The combined organic washingswere washed with brine (100 mL), dried over Na₂SO₄ and concentrated togive 2.63 g of an olive green solid (aniline), which was used withoutfurther purification. To this aniline in acetone (150 mL) and water (20mL) was added NaHCO₃ (1.84 g, 21.9 mmols) and then benzylchloroformate(1.68 mL, 11.8 mmols). After stirring overnight the mixture was pouredinto ice water (100 mL) and the resulting tan precipitate was collectedon a filter, washed with water and dried in a vacuum to give the Cbzaniline as a tan solid (3.50 g, 95% yield). Mp=146-148° C. MS (M+1)=363m/z.

[0116] Step 3:

[0117] To the above Cbz aniline (0.74 g, 2.04 mmols) in THF (10 mL) at−78° C. was added n-BuLi (2.5 M, 0.82 mL, 2.05 mmols) dropwise. Afterstirring for 40 min, (R)-glycidyl butyrate (0.31 mL, 2.10 mmols) in THF(0.5 mL) was added dropwise and the resulting mixture was allowed towarm to RT overnight. A white precipitate had formed and was collectedon a filter and washed with water and ether. Chromatography on silicagel with 25% ethyl acetate/hexane as eluent provided the product as awhite solid (0.58 g, 87% yield). MS (M+1)=329 m/z.

EXAMPLE 2(5R)-3-[4-(1,3-Dihydro-1-oxo-2H-isoindol-2-yl)-3-fluorophenyl]-5-[[(methylsulfonyl)oxy]methyl]-2-oxazolidinone

[0118]

[0119] To the oxazolidinone carbinol from Example 1 (0.58 g, 1.78mmols), in DMF (10 mL) and acetonitrile (10 mL) at 0° C. was addedtriethylamine (0.74 mL, 5.31 mmols) and, after 10 min, methanesulfonylchloride (0.28 mL, 3.62 mmols). After allowing the reaction mixture towarm to RT over an hour starting material was still present so coolingand addition of triethyl amine (0.37 mL, 2.65 mmols) and methanesulfonylchloride (0.14 mL, 1.81 mmols) was repeated. The mixture was poured intowater (50 mL) and extracted with CH₂Cl₂ (6×20 mL), washed with brine(4×10 mL), dried over Na₂SO₄, concentrated to afford the crude productas a brown oil (0.95 g). MS (M+1) =407 m/z.

EXAMPLE 3(5R)-5-(Azidomethyl)-3-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-3-fluorophenyl]-2-oxazolidinone

[0120]

[0121] To the mesylate from Example 2 (0.95 g, 1.78 mmols) in DMF (25mL) was added sodium azide (0.47 g, 7.23 mmols) and heated to 70° C. for16 hrs. After cooling to rt water was added and the mixture extractedwith ethyl acetate (6×25 mL), washed with brine (4×10 mL), dried overNa₂SO₄, concentrated to give 0.48 g of a tan solid. MS (M+1)=354 m/z.

EXAMPLE 4N-[[(5S)-3-[4-(1,3-Dihydro-2H-isoindol-2-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide

[0122]

[0123] The azide from Example 3 in ethyl acetate (25 mL) was placed in aPaar flask and nitrogen bubbled through for 15 min whereupon 10% Pd/C(0.15 g, 0.14 mmol) was added. The mixture was pressurized with 50 psiof H₂ (g) and shaken for 16 hrs whereupon an additional amount of 10%Pd/C (0.15 g, 1.4 mmols) was added and the mixture shaken for anadditional 6 hrs (at this point MS (M+1)=328 m/z). After placing themixture under nitrogen, pyridine (0.22 mL, 2.72 mmol) and then Ac₂O(0.51 mL, 5.30 mmol) were added and the mixture stirred for 2 hrs. Themixture was filtered through celite, washing with ethyl acetate (100mL), concentrated, and chromatographed on silica (gradient elution 1%-5%MeOH/CH₂Cl₂) and then triturated with ethyl acetate (3×3 mL) to give0.19 g of a white solid (Compound 1, 29% yield for 4 steps). Mp=240-242°C. MS (M+1)=370 m/z.

EXAMPLE 5

[0124]

[0125] Step 1:

6,7-Dihydro-6-(2-fluoro-4-nitrophenyl)-5H-pyrrolo[3,4-b]pyridine

[0126] To 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride salt (asdescribed by Petersen, et al. (Bayer) EP0520277A2)(42.8 g, 222 mmols) inDMF (1.2 L) was added 2,4-difluoronitrobenzene (25 mL, 224 mmols). Themixture was heated to 60° C and DIPEA (195 mL, 1.12 mols) was addeddropwise from an addition funnel over 2 hrs. After heating overnight thereaction mixture was cooled to rt, poured into water (3 L), filtered anddried in a vacuum oven (50° C.) to provide a yellow-green solid (53.8 g,94% yield). MS (M+1)=260 m/z.

[0127] Step 2:

6,7-Dihydro-6-(2-fluoro-4-aminophenyl)-5H-pyrrolo[3,4-b]pyridine

[0128] To the above nitro compound (53.8 g, 208 mmol) in THF (175 mL)and methanol (600 mL) was added ammonium formate (59.0 g, 907 mmol).Nitrogen was bubbled through the reaction for approximately 30 minuteswhereupon 10% Pd/C (2.20 g, 21 mmols) was added. After stirringovernight at rt under an atmosphere of nitrogen the reaction mixture wasfiltered through a pad of Celite, washing thoroughly with methanol (400mL), and concentrated to a volume of ca. 200 mL. Water (300 mL) wasadded and the mixture extracted with ethyl acetate (5×200 mL). Thecombined organic layers were washed with brine, dried (Na₂SO₄),filtered, and utilized directly in the next step without furtherpurification. MS (M+1)=230 m/z.

[0129] Step 3:

6,7-Dihydor-6-(2-fluoro-4-(Aminocarboxybenzyl)phenyl)-5H-pyrrolo[3,4-b]pyridine.

[0130] The above aniline (˜208 mmols) in acetone (1 L) and water (160mL) was cooled to 0° C. whereupon sodium bicarbonate (37.4 g, 445 mmols)was added followed by the dropwise addition of benzylchloroformate (34.2mL, 228 mmols). The reaction mixture was allowed to warm to roomtemperature and stirred overnight whereupon a ppt formed. The reactionwas poured into ice water (2 L) and the resulting precipitate wascollected by filtration. The solid was washed with water and dried in avacuum oven (50° C.) to afford the Cbz derivative (73.0 g, 97% yield) asa salmon colored powder. MS (M+1)=364 m/z.

[0131] Step 4:

[0132] (Compound 2). The above Cbz derivative (40.8 g, 112 mmols) in THF(1 L) was cooled to −78° C. under a nitrogen atmosphere. To this mixturewas added n-BuLi (2.5 M, 45.8 mL, 114.5 mmols) dropwise via syringe overfifteen minutes. The reaction was warmed to room temperature and allowedto stir for 45 minutes before again being cooled to −78° C. At thispoint (R)-glycidyl butyrate (17.2 mL, 117 mmols) was added and thereaction mixture allowed to warm to rt overnight during which time aprecipitate formed. The ppt was collected, washed with several portionsof ether (5×100 mL) and dried in a vacuum oven (50° C.) to afford 40.6 gof the ether solvate of the lithium alkoxide as a tan fluffy powder.This material was then washed with several portions of water (4×200 mL)and dried in a vacuum oven (50° C.) to afford the oxazolidinone alcohol(34.1 g, 92% yield) as a tan granular solid. Mp=208-212° C., decomp. MS(M+1)=330 m/z.

EXAMPLE 6

[0133]

[0134] Oxazolidinone Mesylate. The above oxazolidinone carbinol (fromExample 4) (33.8 g, 103 mmols) was suspended in DMF (1.25 L, previouslydegassed with nitrogen) at rt under a nitrogen atmosphere. Triethylamine(50 mL, 360 mmols) was added followed by the dropwise addition ofmethanesulfonyl chloride (13.5 mL, 174 mmols). After stirring for 3 hrsthe reaction mixture was poured into water (200 mL) and methylenechloride (1 L) added. A ppt was filtered off, washed with water (3×200mL) and dried in a vac oven (50° C.) to afford the mesylate as a tansolid (28.1 g, 67%). The organic layer was dried (Na₂SO₄), filtered andevaporated to also afford the mesylate (11.7 g, 28% yield) as a tansolid. Both where characterized with MS (M+1)=408 m/z.

EXAMPLE 7

[0135]

[0136] Oxazolidinone Azide. The above mesylate (from Example 5) (27.8 g,68.2 mmols) and sodium azide (17.7 g, 271 mmols) in anhydrous DMF (1 L),previously degassed with nitrogen, were heated 95° C. for 6 hr under anitrogen atmosphere. After cooling, the mixture was poured into stirredice water (2 L) and formed a flocculant white ppt. The ppt was collectedon a filter and washed with water (4×200 mL), dried in a vac oven (50°C.) to afford the azide as a light beige solid (22.7 g, 94% yield).Mp=175-180° C., decomp. MS (M+1)=355 m/z.

EXAMPLE 8

[0137]

[0138] Oxazolidinone Acetamide. The above azide (from Example 6)(21.67g, 61.16 mmol) dissolved in DMF (400 mL) and THF (500 mL) was degassedwith nitrogen for 30 minutes whereupon 10% Pd/C (4.74 g, 4.4 mmols) wasadded and the reaction hydrogenated on a Parr apparatus (60 psi ofhydrogen) for 14 hr. The reaction mixture was removed from the Parrapparatus and placed under a nitrogen atmosphere whereupon pyridine(5.44 mL, 67.3 mmols) and acetic anhydride (6.35 mL, 67.3 mmols) wereadded. After stirring for 1 hr the reaction mixture was filtered througha pad of Celite, washing thoroughly with methanol and then copiousamounts of 50% MeOH/CH₂Cl₂ (ca. 2 L). The filtrate was evaporated toafford the crude acetamide in DMF. The mixture was slowly added to water(2 L) and the ppt collected on a filter, washed with water (5×400 mL)and dried in a vac oven (50° C.) to provide the acetamide as ananalytically pure white solid (14.2 g, 63% yield). The combinedfiltrates were extracted with methylene chloride (5×200 mL), dried overNa₂SO₄ and concentrated. Water was added to the residue and theresulting ppt was filtered off and dried in a vac oven (50° C.) toafford a second crop of the acetamide as a light tan, fluffy solid (5.61g, 25%). For the analytically pure material Mp=229-230° C., decomp. MS(M+1)=371 m/z.

EXAMPLE 9

[0139]

[0140] The above acetamide from Example 8 (2.51 g, 6.78 mmols) was takenup in CH₂Cl₂ and MnO₂ added (23.9 g, 234 mmols). After stirringovernight the reaction mixture was filtered through celite, concentratedand chromatography on silica with 10% MeOH/CH₂Cl₂ as eluent to affordthe product as a light yellow solid (0.48 g, 19% yield). Mp=220-225° C.decomp. MS (M+1)=369 m/z.

EXAMPLE 10

[0141]

[0142] Compound 5 was prepared as in Example 8 except (S)-glycidylbutyrate was employed in the oxazolidinone formation. The product wasisolated as a light tan solid. Mp=227-230° C. decomp. MS (M+1) 371 m/z.

EXAMPLE 11

[0143]

[0144] Compound 6 was prepared as in Example 9 and isolated as a lightyellow solid. Mp=181-185° C. decomp. MS (M+1)=369 m/z.

EXAMPLE 12

[0145]

[0146] To 5-hydroxyisoxazole (prepared as in Chem Pharm Bull 1966,14(11), 1277) (0.174 g, 2.04 mmols) in DMF was added NaH (60% inoil)(0.105 g, 2.62 mmols). After stirring for 30 min the mesylate (fromExample 6) (0.744g, 1.82 mmols) was added in one portion and the mixturestirred at 60° C. overnight. After cooling to rt water was added and appt was collected on a filter, air dried and chromatographed on silicawith 2.5% MeOH/CH₂Cl₂ as eluent to afford the product as a white solid(0.140 g, 19 % yield). Mp=182-185° C. MS (M+1)=397 m/z.

EXAMPLE 13

[0147]

[0148] To the above oxazolidinone (from Example 12) (0.264 g, 6.66mmols) was taken up in CH₂Cl₂ and MnO₂ added (1.66 g, 16.2 mmols) in twoportions over two days. After stirring for two days the reaction mixturewas filtered through celite, concentrated and chromatographed on silicawith 10% MeOH/CH₂Cl₂ as eluent to afford the product as a light yellowsolid (0.086 g, 32% yield). Mp =133-135° C. MS (M+1)=395 m/z.

EXAMPLE 14

[0149]

[0150] To NaH (60% by wt in oil)(0.03 g, 0.76 mmol) in DMF (5 mL) wasadded oxazolidinone carbinol (from Example 5) (0.23 g, 0.71 mmol) infour portions. After stirring for 30 min 2-chloropyrazine (0.065 mL,0.71 mmol) was added via syringe and stirred overnight at rt. Water wasadded and a ppt was collected on a filter, air dried and chromatographedon silica with 5% MeOH/CH₂Cl₂ as eluent to afford the product as a whitesolid (0.067 g, 23% yield). Mp=225-230° C. MS (M+1)=408 m/z.

EXAMPLE 15

[0151]

[0152] The above oxazolidinone (from Example 14) (0.024 g, 0.058 mmol)in CH₂Cl₂ (5 mL) was added MnO₂ (0.07 g, 0.7 mmol). After stirringovernight the reaction mixture was filtered through Celite andconcentrated to afford the product as a very light yellow solid (0.015g, 64% yield). Mp=192-194° C. MS (M+1)=406 m/z.

EXAMPLE 16

[0153]

[0154] To a suspension of the oxazolidinone carbinol (prepared inExample 5) (330 mg, 1.0 mmol), triphenylphosphine (260 mg, 1.1 mmols)and 4-hydroxy-1, 2, 5-thiadiazole (100 mg, 1.0 mmol) (as prepared in U.SPat. No. 3,391,150 [Jul. 2, 1968]) in THF (8 mL) was addeddiisopropylazodicarboxylate (0.20 mL, 1.1 mmols). After stirringovernight at rt the reaction mixture was filtered, washed with methanol,and air dried to afford a yellow crystalline solid (60 mg, 15% yield).Mp=185-187° C. MS (M+1)=414 m/z.

EXAMPLE 17

[0155]

[0156] To the oxazolidinone (prepared in Example 16) (160 mg, 0.39 mmol)suspended in CH₂Cl₂ (1.0 mL) was added MnO₂ (four additions of 150 mgover four days). The reaction mixture was filtered through a plug ofCelite, washed with CH₂Cl₂ (15 mL), and concentrated under reducedpressure to afford the product as a white crystalline solid (63 mg, 40%yield). Mp=185-188° C. MS(M+1)=412m/z.

EXAMPLE 18

[0157]

[0158] To the amine (as prepared in Example 8) (100 mg, 0.30 mmol) andpotassium carbonate (100 mg, 0.72 mmol) suspended in methanol (1.0 mL),was added propionyl chloride (50 mg, 0.54 mmol). After stirringovernight at 80° C. the reaction mixture was cooled and water was added.A precipitate was filtered off, washed with methanol and air dried toafford the product as a brown crystalline solid (15 mg, 13 % yield). Mp110-1 12° C. MS (M+1) 385 m/z.

EXAMPLE 19

[0159]

[0160] To the amide (prepared in Example 18) (15 mg, 0.04 mmol)suspended in CH₂Cl₂ (1.0 mL), was added MnO₂ (200 mg) at rt. Afterstirring overnight, the reaction mixture was filtered through a plug ofCelite, washed with CH₂Cl₂ (10 mL), and concentrated under reducedpressure to afford the product as an light brown crystalline solid (1.6mg, 8% yield). MS (M+1)=383 m/z.

EXAMPLE 20

[0161]

[0162] To the amine (as prepared in Example 8) (60 mg, 0.18 mmol) andpotassium acetate (60 mg, 0.61 mmol) suspended in methanol (1.0 mL), wasadded cyclopropyl carbonyl chloride (120 mg, 1.15 mmols). After stirringat rt overnight, the reaction mixture was filtered, rinsed withmethanol, and then concentrated to dryness under reduced pressure. Theresulting solid residue was triturated with water and filtered to affordthe product as a brown crystalline solid (36 mg, 50% yield). Mp=235-240°C. MS (M+1)=397 m/z.

EXAMPLE 21

[0163]

[0164] To the amide (prepared in Example 20) (36 mg, 0.09 mmol)suspended in CH₂Cl₂ (1.0 mL), was added MnO₂ (three portions of 100 mgover three days) at rt. The reaction mixture was filtered through a plugof Celite, washed with CH₂Cl₂ (10 mL), and concentrated under reducedpressure to afford the product as an off-white crystalline solid (3 mg,8% yield). MS (M+1)=395 m/z.

EXAMPLE 22

[0165]

[0166] To the amine (prepared in Example 8) (60 mg, 0.18 mmol) andpotassium acetate (60 mg, 0.61 mmol) suspended in methanol (1.0 mL), wasadded dropwise methyl chloroformate (120 mg, 1.27 mmols). After stirringfor four hours at rt, the reaction mixture was filtered, diluted withwater, and concentrated under reduced pressure to remove the methanol.The aqueous solution was extracted with ethyl acetate (5×5 mL). Thecombined organics were washed with water, dried over MgSO₄, filtered,and concentrated to provide an oil which was triturated with ether toafford a brown crystalline solid (35 mg, 50% yield). MS (M+1)=387 m/z.

EXAMPLE 23

[0167]

[0168] To the carbamate (prepared in Example 22) (33 mg, 0.08 mmol)suspended in CH₂Cl₂ (1.0 mL), was added MnO₂ (150 mg). After stirringovernight at rt the reaction mixture was filtered through a plug ofCelite, washed with CH₂Cl₂ (10 mL), and concentrated under reducedpressure to afford the product as a yellow crystalline solid (6.0 mg,18% yield). MS (M+1)=385 m/z.

EXAMPLE 24

[0169]

[0170] To the amine (prepared in Example 8) (60 mg, 0.18 mmol) andpotassium acetate (60 mg, 0.61 mmol) suspended in methanol (1.0 mL) wasadded dropwise ethyl chloroformate (0.1 mL, 1.04 mmols). After stirringovernight at rt the reaction mixture was filtered, diluted with water,and concentrated under reduced pressure to remove the methanol. Theaqueous solution was extracted with ethyl acetate (5×5 mL). The combinedorganics were washed with water, dried over MgSO₄, filtered, andconcentrated. The resulting semi-solid was treated with water, filteredand air-dried to afford a brown crystalline solid (18 mg, 30% yield). MS(M+1)=401 m/z.

EXAMPLE 25

[0171]

[0172] To the amine (prepared in Example 8) (95 mg, 0.29 mmol) suspendedin pyridine (0.5 mL) was added methane sulfonylchloride (0.08 mL, 1.0mmol). After stirring overnight at rt the pyridine was removed under astream of nitrogen. The residue was treated with water, filtered andair-dried to afford a brown solid (45 mg, 38% yield). Mp=172-176° C. MS(M+1)=407 m/z.

EXAMPLE 26

[0173]

[0174] To the sulfonamide (prepared in Example 25) (10 mg, 0.02 mmol)suspended in CH₂Cl₂ (1.0 mL), was added MnO₂ (100 mg, 10 mmols). Afterstirring overnight the reaction mixture was filtered through a plug ofCelite, washed with CH₂Cl₂ (10 mL), and concentrated under reducedpressure to afford the product as a brown crystalline solid (0.5 mg, 5%yield). MS (M+1)=405 m/z.

EXAMPLE 27

[0175]

[0176] To the amine (prepared in Example 8) (200 mg, 0.61 mmol)suspended in toluene (8 mL), was addeddimethyl-N-cyanodithioiminocarbonate (89 mg, 0.61 mmol). After stirringovernight at reflux the toluene was decanted and the oily residuetreated with methanol, filtered, and air-dried to afford a browncrystalline solid (62 mg, 20% yield). Mp 204-207° C. MS (M+1)=427 m/z.

EXAMPLE 28

[0177]

[0178] A suspension of the thioimidate (from Example 27) (45 mg, 0.10mmol) and MnO₂ (200 mg, 2.0 mmols) in CH₂Cl₂ were stirred at rt for oneday whereupon a second addition of MnO₂ (150 mg, 1.5 mmols) was added.After an additional day of stirring the mixture was filtered throughCelite, washed with CH₂Cl₂ (10 mL), concentrated to afford a yellowcrystalline solid (20 mg, 45% yield). MS (M+1)=426 m/z.

EXAMPLE 29

[0179]

[0180] A suspension of the amine (prepared in Example 8) (165 mg, 0.5mmol) and 2-methyl-1-nitro-2-thiopseudourea (94 mg, 0.70 mmol) (asprepared as in EP 0539204/1993) in methanol (2 mL) was refluxed for fourhours. After cooling to rt the reaction mixture was filtered and airdried to afford a yellow crystalline solid (50 mg, 24% yield).Mp=202-206° C. MS (M+1)=416 m/z.

EXAMPLE 30

[0181]

[0182] To the nitroguanidine (prepared in Example 29) (35 mg, 0.08 mmol)suspended in CH₂Cl₂ (1.0 mL) was added MnO₂ (three additions of 100 mgover three days). The reaction mixture was filtered through a plug ofCelite, washed with CH₂Cl₂ (10 mL), and concentrated under reducedpressure to afford the product as a yellow crystalline solid (1.6 mg, 4%yield). MS (M+1)==414 m/z.

EXAMPLE 31

[0183]

[0184] The starting material 6,7-dihydro-5H-pyrrolo[3,4-c]pyridine wasprepared as in U.S. Pat. No. 5,371,090 to Petersen et al. Compound 26was then prepared as in Example 8 except the acetamide wasrecrystallized from acetonitrile to give a light tan solid. Mp=182-190°C. decomposition. MS (M+1)=371 m/z.

EXAMPLE 32

[0185]

[0186] Compound 27 was isolated from the final step of Example 31 viachromatography (5% MeOH/CH₂Cl₂ as eluent) of the mother liquorscollected from recrystallization. Light yellow solid, Mp=219-225° C.decomp. MS (M+1)=385 m/z.

EXAMPLE 33

[0187]

[0188] Compound 28 was prepared as in Example 9 except with 10%MeOH/CH₂Cl₂ as eluent. Light yellow solid, Mp=219-225° C. decomposition.MS (M+1)=369 m/z.

EXAMPLE 34

[0189]

[0190] Isothiazole (0.088 g, 0.87mmol)(prepared as in J HeterocyclicChem 1971, 8, 591) was added portionwise at rt to a suspension of sodiumhydride (0.036 g, 0.91 mmol, 60% in oil) in DMF (4 mL) under nitrogen.The mixture was stirred for 30 minutes whereupon the mesylate fromExample 31 (0.31 g, 0.76 mmol), in DMF (10 mL), was added all at once.After stirring for 6 hours at 60° C. the reaction mixture was cooled tort, diluted with water (50 mL), and extracted with ethyl acetate (3×50mL). The combined organics were washed several times with water, thenonce with brine, dried over sodium sulfate, concentrated, andchromatographed on silica with 5% MeOH/EtOAc as eluent. Two productswere isolated from the chromatography: 0.050g of Compound 29; and 0.022g of Compound 30. Overall yield, 30%.

[0191] Compound 29 MS (M+1)=413.0

[0192] Compound 30 MS (M+1)=411.1

EXAMPLE 35

[0193]

[0194] To a suspension of sodium hydride (0.036 g, 0.91mmol, 60% in oil)in DMF (4 mL) at rt under nitrogen was added portion wise4-hydroxy-1,2,5-thiadiazole (0.088 g, 0.87 mmol) (as prepared in U.S.Pat. No. 3,391,150 [Jul. 2, 1968]). After stirring for 30 min themesylate from Example 31 (0.310 g, 0.76 mmol), in DMF (10 mL), was addedall at once. After stirring for 6 hours at 60 C. the reaction mixturewas cooled to rt, diluted with water (50 mL), and extracted with ethylacetate (3×50 mL). The combined organics were washed several times withwater, then once with brine, dried over sodium sulfate, concentrated,and chromatographed on silica with 2% MeOH/EtOAc as eluent. Two productswere isolated from the chromatography: 0.035 g of Compound 31; and0.0093 g of Compound 32. Overall yield, 14%.

[0195] Compound 31 MS (M+1)=414.0

[0196] Compound 32 MS (M+1)=412.1

EXAMPLE 36

[0197]

[0198] Step 1:

[0199] To the mesylate from Example 31 (2.45 g, 6.01 mmol) dissolved indegassed DMF (100 mL) under nitrogen was added potassium phthalimide(2.23 g, 12.0 mmols). After heating at 65° C. for 3 hours the reactionmixture was cooled, poured into water (300 mL), and extracted withmethylene chloride (3×200 mL). The combined organics were washed withwater (3×150 mL) dried over sodium sulfate, concentrated to a tan solid.This solid was washed with water and dried in a high vacuum oven at 50°C. to afford 2.20 g (80%) of the oxazolidinone phthalimide. MS=459.1(M+1)

[0200] Step 2:

[0201] To the above phthalimide (0.97 g, 2.1 mmols) in degassed methanol(30 mL) under nitrogen was added hydrazine monohydrate (0.2 mL, 4.3mmols) dropwise. After refluxing for 12 hours the reaction mixture wascooled to rt, and concentrated, suspended CH₂Cl₂ and filtered. The crudeoxazolidinone amine was concentrated and used without furtherpurification.

[0202] Step 3:

[0203] Compound 33,

[0204] To the crude amine (0.14 g, 0.44 mmol) in CH₂Cl₂ (5 mL) was addedpyridine (0.14 mL, 18 mmols) followed by propionyl chloride (0.76 mL,0.88 mmol). After stirring for 5 hrs at rt the solution was poured intowater (20 mL) and extracted with methylene chloride (3×10 mL). Thecombined extracts were washed with water (10 mL) and 1 M NaOH (aq) (10mL), dried over sodium sulfate, concentrated and chromatographed usingneat EtOAc as eluent to afford the propionyl amide as a gold oil (0.020g, 12% yield). MS=385.2 (M+1)

EXAMPLE 37

[0205]

[0206] To the crude amine (as prepared in Example 36) (0.144 g, 0.437mmol) in methylene chloride (5 mL) was added pyridine (0.14 mL, 1.7mmols), followed by cyclopropane carbonyl chloride (0.08 mL, 0.88 mmol).After stirring for 5 hrs at rt the solution was poured into water (20mL) and extracted with methylene chloride (3×10 mL). The combinedextracts were washed with water (10 mL) and 1 M NaOH (aq) (10 mL), driedover sodium sulfate, concentrated and chromatographed using a gradientelution of 1% to 5% to 10% MeOH/EtOAc. The desired product eluted with5% MeOH/EtOAc and was concentration to afford the product as a whitepowder (0.012 g, 7% yield). MS=397.2 (M+1)

EXAMPLE 38

[0207]

[0208] Step 1:

[0209] To N-[(3-pyrrolidinone-3-fluorophenyl) 5-oxazolidinyl]methylacetamide (prepared according to WO96/13502)(0.150 g, 0.447 mmols) wasadded methoxy-bis(dimethylamino)methane (1 mL). After heating at 50° C.for 15 min the reaction mixture was concentrated to provide the crudeβ-ketoenamine which was used without further purification.

[0210] Step 2;

[0211] Compound 35

[0212] To ethanolic NaOEt (made from 0.027 g Na in 3 mL EtOH) was addedacetamidine hydrochloride (0.113 g, 1.19 mmols) and the aboveβ-ketoenamine oxazolidinone acetamide. After refluxing for 3 hrs thereaction mixture was cooled to rt, concentrated, taken up in chloroform,and washed with water (3×8 mL). After drying over sodium sulfate thecrude product was concentrated, dissolved in 5% MeOH/EtOAc, and filteredto afford the product as an off-white solid (0.052 g, 45% yield).Mp=234° C., decomp. MS=385.9 (M+1)

EXAMPLE 39

[0213]

[0214] To N-[(3-pyrrolidinone-3-fluorophenyl) 5-oxazolidinyl]methylacetamide (prepared according to WO96/13502)(0.099 g, 0.29 mmol) wasadded methoxy-bis(dimethylamino)methane (1.0 mL). After heating at 50°C. for 2 hrs the reaction mixture was concentrated to provide the crudeβ-ketoenamine. To this mixture was added benzene (5 mL), DMF (1 mL) andformamidine acetate (0.55 g, 5.3 mmols). After heating overnight at 95°C. the reaction mixture was cooled to rt and water (8 mL) was added. Appt formed and was collected by filtration, dried in a vacuum oven (50°C.), and chromatographed on silica with 5% MeOH/CH₂Cl₂ as eluent toafford the product as a white powder (0.037 g, 34% yield). Mp=230-232°C. MS (M+1)=372 m/z.

EXAMPLE 40

[0215]

[0216] The above acetamide from Example 39 (0.020 mg, 0.054 mmol) wastaken up in CH₂Cl₂ (5 mL) and MnO₂ added (0.10 g, 0.98 mmol). Afterstirring overnight at rt the reaction mixture was filtered throughCelite and concentrated to afford the product as a light yellow solid(0.016 g, 80% yield). Mp=164-166° C. MS(M+1)=370m/z.

EXAMPLE 41

[0217]

[0218] To the β-ketoenamine (prepared as in Example 39) was addedbenzene (5 mL), DMF (1 mL) and pyrazine-2-carboxamidine hydrochloride(0.62 g, 3.9 mmols). After heating overnight at 95° C. the reactionmixture was cooled to rt and water (8 mL) was added. A ppt formed andwas collected by filtration, dried in a vacuum oven (50° C.), andchromatographed on silica with 5% MeOH/CH₂Cl₂ as eluent to afford theproduct as a light yellow solid (0.0026 g, 2% yield). Mp=212-214° C. MS(M+1)=450 m/z.

EXAMPLE 42

[0219]

[0220] The above acetamide from Example 39 (0.040 g, 0.088 mmols) wastaken up in CH₂Cl₂ (10 mL) and MnO₂ (0.36 g, 3.5 mmols) added in threeportions over three days. After stirring for three days the reactionmixture was filtered through Celite, concentrated and chromatography onsilica with 7% MeOH/CH₂Cl₂ as eluent. Two products were isolated fromthe chromatography: 0.001 g of Compound 39 as a light yellow solid (4%yield); and 0.002 g of Compound 40 as a yellow solid (4% yield).

[0221] Compound 39: MS (M+1)=448 m/z.

[0222] Compound 40: MS (M+1)=464 m/z.

EXAMPLE 43

[0223]

[0224] To the β-ketoenamine (prepared as in Example 39) was addedbenzene (5 mL), DMF (1 mL) and 4-amidinopyridine hydrochloride (0.81 g,5.2 mmols). After heating overnight at 95° C. the reaction mixture wascooled to rt and water (8 mL) was added. A ppt formed and was collectedby filtration, dried in a vacuum oven (50° C.), and chromatographed onsilica with 5% MeOH/CH₂Cl₂ as eluent to afford the product as a lightyellow solid (0.072 g, 55% yield). Mp=245-250° C., decomp. MS (M+1)=449m/z.

EXAMPLE 44

[0225]

[0226] To the β-ketoenamine (prepared as in Example 39) was addedbenzene (5 mL), DMF (1 mL) and 2-amidinopyridine hydrochloride (0.61 g,3.9 mmols) . After heating overnight at 95° C. the reaction mixture wascooled to rt and water (8 mL) was added. A ppt formed and was collectedby filtration, dried in a vacuum oven (50° C.), and chromatographed onsilica with 5% MeOH/CH₂Cl₂ as eluent to afford the product as a yellowpowder (0.054 g, 40% yield). Mp=216-220° C. MS (M+1)=449 m/z.

EXAMPLE 45

[0227]

[0228] To the β-ketoenamine (prepared as in Example 39) was addedbenzene (5 mL), DMF (2 mL) and 3-amidinopyridine hydrochloride (0.49 g,3.1 mmols). After heating overnight at 95° C. the reaction mixture wascooled to rt and water (8 mL) was added. A ppt formed and was collectedby filtration, dried in a vacuum oven (50° C.), and chromatographed onsilica with 5% MeOH/CH₂Cl₂ as eluent to afford the product as a lightpurple, crystalline solid (0.044 g, 33% yield). Mp=265-270° C., decomp.MS (M+1)=449 m/z.

EXAMPLE 46

[0229]

[0230] To the β-ketoenamine (prepared as in Example 39) was addedbenzene (5 mL), DMF (2 mL) and hydrazine hydrochloride (0.22 g, 3.2mmols). After heating overnight at 95° C. the reaction mixture wascooled to rt and water (8 mL) was added. A ppt formed and was collectedby filtration, dried in a vacuum oven (50° C.), and chromatographed onsilica with 5% MeOH/CH₂Cl₂ as eluent to afford the product as off-whitepowder (0.022 g, 21% yield). Mp=244-247° C., decomp. MS (M+1)=360 m/z.

EXAMPLE 47

[0231]

[0232] To the β-ketoenamine (prepared as in Example 39) was addedbenzene (5 mL), DMF (2 mL) and n-propylhydrazine oxalate (0.87 g, 5.3mmols). After heating overnight at 95° C. the reaction mixture wascooled to rt and water (8 mL) was added. A ppt formed and was collectedby filtration, dried in a vacuum oven (50° C.), and chromatographed onsilica with 5% MeOH/CH₂Cl₂ as eluent to afford the product as a lightyellow solid (0.081 g, 55% yield). Mp=204-208° C. MS (M+1)=402 m/z.

EXAMPLE 48

[0233]

[0234] The starting material aniline(N-[[(5S)-3-(4-amino-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]-acetamide)was prepared as in World Patent WO 96/23788. To phthalicdicarboxaldehyde (0.0522 g, 0.378 mmol) in acetonitrile (1 mL) was addedglacial acetic acid (0.05 mL, 0.87 mmol) and then the above aniline(0.0955 g, 0.357 mmol) in acetonitrile (5 mL) dropwise. After 4 hrswater (10 mL) was added and a precipitate was collected on a filter andwashed with water and ether to provide Compound 46 as a light greensolid (0.0655 g, 48%). Mp=211-214° C. MS (M+1)=384 m/z.

EXAMPLE 49

[0235]

[0236] To starting material aniline(N-[[(5S)-3-(4-amino-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]-acetamide)(0.095 g, 0.36 mmol) (as prepared in World Patent WO 96/23788) in CH₂Cl₂(5 mL) was added triethylamine (0.15 mL, 1.1 mmols) and phthaloyldichloride (0.056 mL, 0.39 mmol). After stirring overnight a solid wascollected on a filter, washed with water (10 mL) and dried in vacuumoven (50° C.) to afford the product as a off-white solid (0.060, 42%).Mp=240-242° C. MS (M+1) 398 m/z.

EXAMPLE 50

[0237]

[0238] To starting material aniline(N-[[(5S)-3-(4-amino-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]-acetamide)(0.20 g, 0.75 mmol) (as prepared in World Patent WO 96/23788) inacetonitrile (5 mL) was added 2,3-pyridine dicarboxaldehyde (0.10 g, 6.6mmols) and glacial acetic acid (0.050 mL, 0.87 mmol). After stirring for5 hrs the reaction mixture was concentrated and chromatographed onsilica with 2.5% MeOH/CH₂Cl₂ as eluent to afford the two products: 0.035g of Compound 52 (12%) as a yellow solid; and 0.011 g of Compound 53(4%) as a yellow solid.

[0239] Compound 48: Mp=230-232° C. MS (M+1)=385 m/z.

[0240] Compound 49: Mp=207-209° C. MS (M+1)=385 m/z.

EXAMPLE 51

[0241]

[0242] To the crude β-ketoenamine from Example 38 (˜0.276 mmol) wasadded benzene (5 mL), DMF (2 mL), methylhydrazine (0.15 mL, 2.8 mmols)and HCl in ether (2.75 mL, 1.0 M). After heating overnight at 90° C. thereaction mixture was cooled to rt and water (8 mL) was added. A pptformed and was collected on a filter, dried in a vacuum oven (50° C.),and chromatographed on silica with 10% MeOH/CH₂Cl₂ as eluent to affordthe product as a light yellow solid (0.0285 g, 28% yield). Mp=211-213°C. MS (M+1)=374 m/z.

EXAMPLE 52

[0243]

[0244] To the crude β-ketoenamine from Example 38 (0.282 mmol) was addedbenzene (3 mL), DMF (2 mL), 2-hydrazinopyridine (0.3214 g, 2.8 mmols)and HCl in ether (2.85 mL, 1.0 M). After heating overnight at 90° C. thereaction mixture was cooled to rt and water (8 mL) was added. A pptformed and was collected on a filter, dried in a vacuum oven (50° C.),and chromatographed on silica with 10% MeOH/CH₂Cl₂ as eluent to affordthe product as a tan solid (0.0046 g, 4% yield). Mp=259-261° C. decomp.MS (M+1)=437 m/z.

EXAMPLE 53

[0245]

[0246] To the crude β-ketoenamine from Example 38 (0.2481 mmol) wasadded benzene (3 mL), DMF (2 mL), and tert-butylhydrazine hydrochloride(0.3090 g, 2.48 mmols). After heating overnight at 90° C. the reactionmixture was cooled to RT and water (8 mL) was added. A ppt formed andwas collected on a filter, dried in a vacuum oven (50° C.), andtriturated with 10% MeOH/CH₂Cl₂ to afford the product as a light yellowglassy solid (0.0570 g, 55% yield). Mp=155-157° C. MS (M+1)=416 m/z.

EXAMPLE 54

[0247]

[0248] To the crude β-ketoenamine from Example 38 (˜0.298 mmol) wasadded benzene (3 mL), DMF (2 mL), 2-hydroxyethylhydrazine (0.23 mL, 3.4mmols) and HCl in ether (3.00 mL, 1.0 M). After heating overnight at 90°C. the reaction mixture was cooled to RT and water (8 mL) was added. Appt formed and was collected on a filter, dried,in a vacuum oven (50°C.), and chromatographed on silica with 10% MeOH/CH₂Cl₂ as eluent toafford the product as a light yellow solid (0.0517 g, 43% yield).Mp=163-165° C. MS (M+1)=404 m/z.

EXAMPLE 55

[0249]

[0250] To Compound 44 (0.0481 g, 0.134 mmol) in DMF at RT was addedsodium hydride (60% in oil) (0.008 g, 0.2 mmol) and the mixture stirredfor 20 min. To this mixture was added 2-(diethylamino) ethyl chloride(0.16 mL, 1.0 M in benzene) and the mixture was stirred at 40° C.overnight. The mixture was treated with sat. aqueous NH₄Cl (10 mL) andwater (5 mL). The mixture was extracted with EtOAc (10×20 mL), driedover Na₂SO₄, concentrated and chromatographed on silica with 10%MeOH/CH₂Cl₂ as eluent to afford the two products. The isomer that elutedfirst was identified as Compound 54 and was isolated as a light yellowoil (0.0054 g, 9%). The slower eluting isomer, Compound 55, was isolatedas a light yellow solid (0.0107 g, 17% yield).

EXAMPLE 56

[0251]

[0252] To Compound 44 (0.1098 g, 0.306 mmol) in DMF (4 mL) at RT wasadded sodium hydride (60% in oil) (0.018 g, 0.45 mmol) and the mixturestirred for min whereupon Mel (23.0 μL, 0.369 mmol) was added. Themixture of regioisomers (as shown by ¹H NMR) was stirred for 2 h andthen poured into ice water. A ppt formed and was collected on a filter,dried in a vacuum oven (50° C.), and chromatographed on silica with 2.5%MeOH/CH₂Cl₂ as eluent to afford the product as a white solid (0.0215 g,19%). Mp=234-238° C. MS (M+1)=374 m/z.

EXAMPLE 57

[0253]

[0254] To Compound 44 (0.0701 g, 0.195 mmol) in DMF (3 mL) at RT wasadded sodium hydride (60% in oil) (0.014 g, 0.34 mmol) and the mixturestirred for 30 min whereupon chloroacetonitrile (17.5 μL, 0.276 mmol)was added. The mixture was stirred for 2 h and then poured into icewater. A ppt formed and was collected on a filter, dried in a vacuumoven (50° C.), and recrystallized from methanol to provide the productas a tan solid (0.0102 g, 13%). MS (M+1)=399 m/z.

EXAMPLE 58

[0255]

[0256] To Compound 44 (0.0744 g, 0.207 mmol) in DMF (3 mL) at RT wasadded sodium hydride (60% in oil) (0.015 g, 0.37 mmol) and the mixturestirred for 30 min whereupon chloropyrazine (26.5 μL, 0.299 mmol) wasadded. The mixture was stirred overnight and then poured into ice water.A ppt formed and was collected on a filter, dried in a vacuum oven (50°C.), and triturated with methanol to provide the product as a tan solid(0.0418 g, 46%). MS (M+1)=438 m/z.

EXAMPLE 59

[0257]

[0258] To Compound 44 (0.0676 g, 0.188 mmol) in DMF (3 mL) at RT wasadded sodium hydride (60% in oil) (0.018 g, 0.45 mmol) and the mixturestirred for 30 min whereupon 2-chloropyrimidine (0.0391 g, 0.324 mmol)was added. The mixture was stirred overnight and then poured into icewater. A ppt formed and was collected on a filter, dried in a vacuumoven (50° C.), and triturated with methanol to provide the product as atan solid (0.0214 g, 26%). MS (M+1)=438 m/z.

EXAMPLE 60

[0259]

[0260] To Compound 44 (0.0712 g, 0.198 mmol) in DMF (3 mL) at RT wasadded KOtBu (in THF) (0.26 mL, 1.0 M) and the mixture stirred for 30 minwhereupon 2-(methylamino)ethyl chloride (in benzene) (0.24 mL, 1.0 M)was added. The mixture was stirred overnight and then poured into icewater. The mixture was extracted with EtOAc (10×20 mL), dried overNa₂SO₄, concentrated and chromatographed on silica with 10% MeOH/CH₂Cl₂as eluent to afford two products. The isomer that eluted first wasidentified as Compound 60 and was isolated as a light yellow glass(0.0074 g, 9%). The slower eluting isomer (Compound 61) was isolated asa light yellow glass (0.0269 g, 32% yield). Both: MS (M+1)=431 m/z.

EXAMPLE 61

[0261]

[0262] To Compound 44 (0.989 g, 0.275 mmol) in DMF (4 mL) at RT wasadded KOtBu (in THF) (0.36 mL, 1.0 M) and the mixture stirred for 30 minwhereupon Etl (26.4 μL, 0.330 mmol) was added. The mixture was stirredfor 2 h and then poured into ice water. A ppt formed, and was collectedon a filter and dried in a vacuum oven (50° C.). The mixture ofregioisomers (as shown by ¹H NMR) was chromatographed on silica with2.5% MeOH/CH₂Cl₂ as eluent to afford the product as a white solid(0.0016 g, 2%). MS (M+1)=388 m/z.

EXAMPLE 62

[0263]

[0264] To Compound 44 (0.1120 g, 0.312 mmol) in DMF (3 mL) at RT wasadded KOtBu (in THF) (0.40 mL, 1.0 M) and the mixture stirred for 30 minwhereupon 4-(2-chloroethyl) morpholine (in benzene) (0.37 mL, 1.0 M) wasadded. The mixture was stirred overnight and then poured into ice water.The mixture was extracted with EtOAc (10×20 mL), dried over Na₂SO₄,concentrated and chromatographed on silica with 5->10% MeOH/CH₂Cl₂ aseluent to afford the two products. The isomer that eluted first wasidentified as Compound 63 and was isolated as a light yellow glass(0.0102 g, 7%). The slower eluting isomer (Compound 64) was isolated asa light yellow solid (0.0518 g, 35% yield), Mp=180-190° C. decomp. Both:MS (M+1)=473 m/z.

EXAMPLE 63

[0265]

[0266] To Compound 44 (0.0793 g, 0.221 mmol) in DMF (2.5 mL) at RT wasadded Cs₂CO₃ (0.71 g, 2.2 mmols) and the mixture stirred for 15 minwhereupon 2-chloroethanol (20 μL, 0.30 mmol) was added. The mixture wasstirred overnight and then poured into ice water. A ppt formed and wascollected on a filter and dried in a vacuum oven (50° C.) to provide theproduct as a light yellow solid (0.0632 g, 70%). Mp=232-242° C., decomp.MS (M+1)=404 m/z.

EXAMPLE 64

[0267]

[0268] To Compound 44 (0.1546 g, 0.430 mmol) in DMF (3 mL) at RT wasadded Cs₂CO₃ (1.62 g, 5.0 mmols) and the mixture stirred for 15 minwhereupon (R)-(−)-3-chloro-1,2-propanediol (45 μL, 0.54 mmol) was added.The mixture was stirred overnight and then poured into ice water. A pptformed and was collected on a filter and dried in a vacuum oven (50° C.)to provide the product as a light yellow solid (0.1316 g, 70%).Mp=188-191° C. MS (M+1)=434 m/z.

EXAMPLE 65

[0269]

[0270] To Compound 44 (0.1524 g, 0.424 mmol) in DMF (3 mL) at RT wasadded KOtBu (in THF) (0.55 mL, 1.0 M) and the mixture stirred for 30 minwhereupon propargyl bromide (80% in toluene) (0.06 mL, 0.54 mmol) wasadded. The mixture was stirred overnight at RT and then poured into icewater. A ppt formed and was collected on a filter and dried in a vacuumoven (50° C.) to provide 0.1483 g of a mixture of regioisomers (as shownby ¹H NMR). A portion of the crude material was chromatographed (40 mgin 0.5 mL DMSO) on reverse-phase HPLC with 5-30% acetonitrile/watercontaining 0.1% TFA as eluent. Pooled fractions containing Compound 67were treated with 10% K₂CO₃ and the acetonitrile removed on a rotovap. Appt formed and was collected on a filter and dried in a vacuum oven (50°C.) to provide the product as a white solid (0.0096 g, est. 21% yield).MS (M+1)=398 m/z.

EXAMPLE 66

[0271]

[0272] To Compound 44 (0.1460 g, 0.406 mmol) in DMF (3 mL) at RT wasadded Cs₂CO₃ (1.26 g, 3.87 mmols) and the mixture stirred for 15 minwhereupon 3-chloropropanol (45 μL, 0.54 mmol) was added. The mixture wasstirred overnight and then poured into ice water. A ppt formed and wascollected on a filter and dried in a vacuum oven (50° C.) to provide theproduct as a light yellow solid (0.1526 g, 90%). Mp=171-173° C. MS(M+1)=418 m/z.

EXAMPLE 67

[0273]

[0274] To Compound 44 (0.3523 g, 0.352 mmol) in DMF (3 mL) at RT wasadded Cs₂CO₃ (1.26 g, 3.87 mmols) and the mixture stirred for 15 minwhereupon (S)-(+)-3-chloro-1,2-propanediol (37 μL, 0.44 mmol) was added.The mixture was stirred overnight and then poured into ice water. A pptformed and was collected on a filter and dried in a vacuum oven (50° C.)to provide the product as a light brown solid (0.0862 g, 90%).Mp=184-188° C. MS (M+1)=434 m/z.

EXAMPLE 68

[0275]

[0276] To Compound 44 (0.1070 g, 0.298 mmol) in DMF (2 mL) at RT wasadded Cs₂CO₃ (0.97 g, 3.0 mmols) and the mixture stirred for 15 minwhereupon 2-iodo-1,1,1-trifluoroethane (37 μL, 0.38 mmol) was added. Themixture was stirred three days whereupon an additional amount of2-iodo-1,1,1-trifluoroethane (37 μL, 0.38 mmol) was added. After twodays the mixture was poured into ice water. A ppt formed and wascollected on a filter, dried in a vacuum oven (50° C.), andchromatographed on silica with 2.5->5% MeOH/CH₂Cl₂ as eluent to affordthe product as a light yellow solid (0.0161 g, 12%). Mp=170-172° C. MS(M+1)=442 m/z.

EXAMPLE 69

[0277]

[0278] To Compound 44 (0.0530 g, 0.148 mmol) in DMF (1 mL) at RT wasadded KOtBu (in THF) (0.20 mL, 1.0 M) and the mixture stirred for 30 minwhereupon benzylbromide (21 μL, 0.18 mmol) was added. The mixture wasstirred overnight and then poured into ice water. A ppt formed and wascollected on a filter and dried in a vacuum oven (50° C.) to provide0.0521 g of a mixture of regioisomers (as shown by ¹H NMR). The crudematerial was chromatographed on reverse-phase HPLC with 5-30%acetonitrile/water containing 0.1% TFA as eluent. Pooled fractionscontaining Compound 71 were treated with 10% K₂CO₃ and the acetonitrileremoved on a rotovap. A ppt formed and was collected on a filter anddried in a vacuum oven (50° C.) to provide the product as a yellow solid(0.0111 g, 17% yield). MS (M+1)=450 m/z.

EXAMPLE 70

[0279]

[0280] To Compound 44 (0.1065 g, 0.296 mmol) in DMF (2 mL) at RT wasadded KOtBu (in THF) (0.40 mL, 1.0 M) and the mixture stirred for 30 minwhereupon (chloromethyl) cyclopropane (33 μL, 0.35 mmol) was added. Themixture was stirred overnight and then poured into ice water. A pptformed and was collected on a filter and dried in a vacuum oven (50° C.)to provide 0.0868 g of a mixture of regioisomers. The crude material waschromatographed on silica with 5% MeOH/CH₂Cl₂ as eluent and thenchromatographed (in 0.5 mL DMSO) on reverse-phase HPLC with 15-25%acetonitrile/water containing 0.1% TFA as eluent. Pooled fractions weretreated with 10% K₂CO₃ and the acetonitrile removed on a rotovap. A pptformed and was collected on a filter and dried in a vacuum oven (50°C.).The earlier eluting compound was identified as Compound 72 (0.0026 g, 2%yield). The later eluting compound was identified as Compound 73 (0.0082g, 7%), a white solid Mp 234-236° C. Both: MS (M+1) 414 m/z.

EXAMPLE 71

[0281]

[0282] To Compound 44 (0.0.45 g, 0.125 mmol) in DMF (2 mL) at RT wasadded KOtBu (in THF) (0.16 mL, 1.0 M) and the mixture stirred for 30 minwhereupon chloroacetone (13 μL, 0.16 mmol) was added. The mixture wasstirred for seven days and resubjected to base and alkylating agent asbefore [KOtBu (in THF) (0.16 mL, 1.0 M) and chloroacetone (13 μL, 0.16mmol)]. After two more days the mixture was poured into ice water. A pptformed and was collected on a filter, dried in a vacuum oven (50° C.),and chromatographed on silica with 5% MeOH/CH₂Cl₂ as eluent to affordthe product as a white solid (0.0087 g, 17%). MS (M+1)=416 m/z.

EXAMPLE 72

[0283]

[0284] To Compound 44 (0.1018 g, 0.283 mmol) in DMF (2 mL) at RT wasadded Cs₂CO₃ (0.92 g, 2.8 mmols) and the mixture stirred for 30 minwhereupon 5-chloromethyl-2-oxazolidinone (0.0511 g, 0.378 mmol) wasadded. The mixture was stirred at 60° C. for six days and then pouredinto ice water. A ppt formed and was collected on a filter and dried ina vacuum oven (5° C.) to provide 0.0429 g of a crude mixture. The crudematerial was chromatographed on reverse-phase HPLC with 5-30%acetonitrile/water containing 0.1% TFA as eluent. Pooled fractions weretreated with 10% K₂CO₃ and the acetonitrile removed on a rotovap. A pptformed and was collected on a filter and dried in a vacuum oven (50°C.)) to provide a white solid as a mixture of diastereomers (asindicated) (0.0054 g, 4%). MS (M+1)=459 m/z.

EXAMPLE 73

[0285]

[0286] To Compound 44 (0.4566 g, 1.27 mmol) in DMF (10 mL) at RT wasadded KOtBu (in THF) (2.54 mL, 1.0 M) and the mixture stirred for 30 minwhereupon tert-butyl bromoacetate (0.38 mL, 2.6 mmol) was added. Themixture was stirred overnight at 35° C. and then poured into ice water.A ppt formed and was collected on a filter and dried in a vacuum oven(50° C.) to provide 0.4404 g of a mixture of regioisomers. The crudematerial (200 mg) was chromatographed on reverse-phase HPLC with 5-20%acetonitrile/water containing 0.1% TFA as eluent. Pooled fractions weretreated with 10% K₂CO₃ and the acetonitrile removed on a rotovap. A pptformed and was collected on a filter and dried in a vacuum oven (50°C.). The earlier eluting compound was identified as Compound 76 (0.0032g, 1%), a white solid Mp=85-90° C. The later eluting compound wasidentified as Compound 77 (0.0505 g, 18% yield) a white solidMp=136-138° C. Both: MS (M+1)=474 m/z.

EXAMPLE 74

[0287]

[0288] To Compound 44 (0.2689 g, 0.748 mmol) in DMF (6 mL) at 35° C. wasadded KOtBu (in THF) (1.50 mL, 1.0 M) and the mixture stirred for 15 minwhereupon propargyl bromide (80% in toluene) (0.17 mL, 1.5 mmol) wasadded. The mixture was stirred overnight at 35° C. and then poured intoice water. A ppt formed and was collected on a filter and dried in avacuum oven (50° C.). The crude material was chromatographed onreverse-phase HPLC with 5-25% acetonitrile/water containing 0.1% TFA aseluent. Pooled fractions were treated with 10% K₂CO₃ and theacetonitrile removed on a rotovap. A ppt formed and was collected on afilter and dried in a vacuum oven (50°C.). Four compounds were separablein the following order, earlier to later eluting: the first compound wasidentified as Compound 78 (0.0082 g, 3%), a white solid Mp 140-142° C.;the second compound was identified as the previous synthesized Compound67 (0.0734 g, 25%), a white solid; the third compound was identified asCompound 79 (0.0101 g, 3%), a white solid Mp=180-182° C.; the fourthcompound was identified as Compound 80 (0.0062 g, 3%), a white solidMp=183-186° C. All: MS (M+1)=398 m/z.

EXAMPLE 75

[0289]

[0290] To Compound 44 (0.0766 g, 0.213 mmol) in DMF (1.5 mL) at RT wasadded KOtBu (in THF) (0.43 mL, 1.0 M) and the mixture stirred for 30 minwhereupon chloromethyltrimethylsilane (61 μL, 0.44 mmol) was added. Themixture was stirred overnight at RT and then poured into ice water. Appt formed and was collected on a filter, dried in a vacuum oven (50°C.), and chromatographed on reverse-phase HPLC with 5-50%acetonitrile/water containing 0.1% TFA as eluent. Pooled fractions weretreated with 10% K₂CO₃ and the acetonitrile removed on a rotovap. A pptformed and was collected on a filter and dried in a vacuum oven (50°C.). The earlier eluting compound was identified as Compound 81 (0.0148g, 16%), a white solid Mp=148-150° C. The later eluting compound wasidentified as Compound 82 (0.0217 g, 23% yield) a white solidMp=151-153° C. Both: MS (M+1)=446 mz.

EXAMPLE 76

[0291]

[0292] To Compound 44 (0.1050 g, 0.292 mmol) in DMF (2 mL) at RT wasadded KOtBu (in THF) (0.58 mL, 1.0 M) and the mixture stirred for 30 minwhereupon (chloromethyl) dimethylphenylsilane (0.12 mL, 0.66 mmol) wasadded. The mixture was stirred overnight at RT and then poured into icewater. The mixture was extracted with EtOAc (6×16 mL), dried overNa₂SO₄, and concentrated. The crude material was chromatographed onreverse-phase HPLC with 5-50% acetonitrile/water containing 0.1% TFA aseluent. Pooled fractions were treated with 10% K₂CO₃ and theacetonitrile removed on a rotovap. A ppt formed and was collected on afilter and dried in a vacuum oven (50° C.). The earlier eluting compoundwas identified as Compound 83 (0.0026 g, 2%), a white solid. The latereluting compound was identified as Compound 84 (0.0064 g, 4% yield) awhite solid. Both: MS (M+1)=508 m/z.

EXAMPLE 77

[0293]

[0294] To Compound 44 (0.0998 g, 0.278 mmol) in DMF (1.5 mL) at RT wasadded KOtBu (in THF) (0.42 mL, 1.0 M) and the mixture stirred for 30 minwhereupon benzyl chloromethyl ether (62.1 μL, 0.417 mmol) was added. Themixture was stirred overnight at 35° C. and then poured into ice water.A ppt formed and was collected on a filter and dried in a vacuum oven(50° C.) to provide 0.1157 g of a mixture of regioisomers. The crudematerial was chromatographed on reverse-phase HPLC with 5-30%acetonitrile/water containing 0.1% TFA as eluent. Pooled fractions weretreated with 10% K₂CO₃ and the acetonitrile removed on a rotovap. A pptformed and was collected on a filter and dried in a vacuum oven (50°C.). The earlier eluting compound was identified as Compound 85 (0.0120g, 9%), a white solid Mp=127-130° C. The later eluting compound wasidentified as Compound 86 (0.0262 g, 20% yield) a white solidMp=156-159° C. Both: MS (M+1) 480 m/z.

EXAMPLE 78

[0295]

[0296] To Compound 44 (0.2983 g, 0.830 mmol) in DMF (9 mL) at RT wasadded KOtBu (in THF) (1.0 mL, 1.0 M) and the mixture stirred for 30 minwhereupon methyl isothiocyanate (0.11 mL, 1.6 mmol) was added. Themixture was stirred overnight at RT and then poured into ice water. Appt formed and was collected on a filter and dried in a vacuum oven (50°C.) to provide 0.2903 g of crude material. A portion of the material(100 mg) was chromatographed on reverse-phase HPLC with 5-25%acetonitrile/water containing 0.1% TFA as eluent. Pooled fractions weretreated with 10% K₂CO₃ and the acetonitrile removed on a rotovap. A pptformed and was collected on a filter and dried in a vacuum oven (50°C.).Compound 87 was isolated as a tan solid (0.0162 g, 13% yield).Mp=246-249° C. MS (M+1)=433 m/z.

EXAMPLE 79

[0297]

[0298] To Compound 57 from Example 57 (0.0955 g, 0.240 mmol) in DMF (1mL) at RT was added dibutyltin oxide (0.0065 g, 0.03 mmol) and thenazidotrimethylsilane (64 μL, 0.48 mmol). The mixture was stirredovernight at 100° C. and then poured into ice water. A ppt formed andwas collected on a filter, dried in a vacuum oven (50° C.), andchromatographed on silica with 10 MeOH/CH₂Cl₂ containing 1% acetic acidas eluent. The product was isolated as a tan solid (0.0379 g, 36%yield). MS (M+1) 442 m/z.

EXAMPLE 80

[0299]

[0300] To Compound 44 (0.110 g, 0.306 mmol), and Cs₂CO₃ (1.03 g, 3.03mmol) in DMF (15 mL) was added 3-picolyl chloride hydrochloride. Afterstirring at RT for 20 hr the reaction was poured into water andextracted with EtOAc (3×30 mL). The organic phases were washed withwater and brine, dried over Na₂SO₄, and concentrated in vacuo to anorange film. The mixture was purified by column chromatography on silicausing 5% methanol/ethyl acetate to afford a mixture of regioisomers (asshown by ¹H NMR). Compound 89 could be purified by preparativereverse-phase HPLC and was isolated as a white powder (7%). MS=451 (M+H)

EXAMPLE 81

[0301]

[0302] The two regioisomers were synthesized by the above procedure,using 2-picolyl chloride hydrochloride. After preparative reverse-phaseHPLC purification, Compound 90 was isolated as a yellow solid (6%) andCompound 91 was isolated as a yellow film (2%). Both MS=451 (M+H)

EXAMPLE 82

[0303]

[0304] To Compound 44 (0.051 g, 0.143 mmol), in DMF (5 mL) was addedKOt-Bu (0.17 mL, 1 M in THF). The reaction was stirred at RT for 10 min,and then allyl bromide (0.014 mL, 0.16 mmol) was added. After 20 minutesthe reaction was poured into water, and extracted with EtOAc (3×50 mL).The combined organics were washed with water, brine, and then dried overMgSO₄. The mixture of regioisomers (as shown by ¹H NMR) was concentratedin vacuo to a yellow residue, and purified by preparative reverse-phaseHPLC to give a colorless film to provide Compound 92 (3%). MS=438 (K+)

EXAMPLE 83

[0305]

[0306] To Compound 44 (1.15 g, 3.20 mmol), in DMF (10 mL) was added(S)-epichlorohydrin (0.28 mL, 3.5 mmol), followed by the dropwiseaddition of KOt-Bu (3.84 mL, 1.0 M in THF) at RT. After 3 hr, thereaction was poured into water (40 mL) and a fine, white powderprecipitated from solution. The powder was collected by filtration,washed with water, and dried in vacuo at 50° C. to give the product as asingle stereoisomer in 63% yield. MS=454 (K+)

EXAMPLE 84

[0307]

[0308] To Compound 44 (0.050 g, 0.139 mmol), in DMF (5 mL) was added(R)-epichlorohydrin (0.01 mL, 0.2 mmol), followed by the dropwiseaddition of KOt-Bu (0.17 mL, 1.0 M in THF) at RT. After 3 hr, thereaction was poured into water (40 mL) and extracted with EtOAc (3×30mL). The combined organics were washed with water, then brine and driedover MgSO₄. The filtrate was concentrated in vacuo to provide the crudeproduct as a yellow solid. The solid was chromatographed on silica using3% methanol/methylene chloride to elute the product as a singlestereoisomer. Compound 94 was isolated as a yellow powder (37%). MS=416(M+H), 438 (Na+)

EXAMPLE 85

[0309]

[0310] To Compound 44 (0.048 g, 0.13 mmol), in DMF (1 mL) was addedK₂CO₃ (0.074 g, 0.54 mmol) and bromopropionitrile (0.013 mL, 0.16 mmol)and the reaction was heated to 50° C. for 40 minutes. Upon cooling, thereaction was added to water (6 mL) and extracted with EtOAc (3×10 mL).The extracts were washed with water, then brine and dried over MgSO₄.The filtrate was concentrated in vacuo. The crude product waschromatographed on silica with 4% methanol/ethyl acetate as eluent toprovide Compound 95 (18%). MS=413 (M+H), 435 (Na+)

EXAMPLE 86

[0311]

[0312] Compound 93 (0.050 g, 0.120 mmol) was dissolved in excesspiperdine (1 mL) and refluxed for 20 hr. The reaction mixture wasconcentrated in vacuo and the resulting residue was extracted with EtOAc(3×10 mL). The organics were washed with water and brine, and dried overNa₂SO₄. The filtrate was concentrated in vacuo to an orange oil that waspurified by silica gel column chromatography. The product eluted with10% methanol/methylene chloride to give a white solid in 20% yield.MS=501. (M+H), 523 (Na+)

EXAMPLE 87

[0313]

[0314] Compound 93 (0.052 g, 0.124 mmol) was dissolved in excessmorpholine (1 mL) and refluxed for 20 hr. The reaction mixture wasconcentrated in vacuo and the resulting residue was extracted with EtOAc(3×10 mL). The organics were washed with water and brine, and dried overNa₂SO₄. The filtrate was concentrated in vacuo to an orange oil that waspurified by silica gel column chromatography. The product eluted with 5%methanol/methylene chloride to give Compound 97 as a white solid in 20%yield. MS=503.3 (M+H), 525.3 (Na+)

EXAMPLE 88

[0315]

[0316] The sodium salt of benzenethiol (0.0456 g, 0.345 mmol) was addedto a solution of Compound 93 (0.120 g, 0.288 mmol) in DMF (10 mL) RT.Upon completion of the reaction as judged by thin layer chromatography,the reaction mixture was poured into water and extracted with EtOAc(3×10 mL). The extracts were washed with water, then brine, and driedover MgSO₄. The filtrate was concentrated in vacuo to afford anoff-white solid in 7% yield. MS=526 (M+H), 548 (Na+)

EXAMPLE 89

[0317]

[0318] To a solution of Compound 93 (0.102 g, 0.246 mmol) in DMF (4 mL)was added Cs₂CO₃ (0.802 g, 2.46 mmol), followed by the dropwise additionof ethanethiol (0.02 mL, 0.295 mmol). After stirring for 3 hr at RTwater (15 mL) was added and the reaction mixture was extracted withEtOAc (3×10 mL). The combined organic extracts were washed with water,then brine, and dried over MgSO₄. The filtrate was concentrated in vacuoto give the crude product as a yellow film. Trituration with methylenechloride/hexanes gave the product as a gold solid (3%). MS=478 (M+H),500 (Na+)

EXAMPLE 90

[0319]

[0320] To a solution of Compound 94 (0.0921 g, 0.222 mmol) in DMF (4 mL)was added Cs₂CO₃ (0.722 g, 2.22 mmol) followed by the dropwise additionof mercaptoethanol (0.02 mL, 0.266 mmol). The reaction mixture wasstirred RT for 20 hr. Water (15 mL) was poured into the reaction and theresulting mixture was extracted with EtOAc (3×10 mL). The combinedextracts were washed with water, then brine, and dried over MgSO₄. Thefiltrate was concentrated in vacuo and purified by silica gel columnchromatography, using 10% methanol/methylene chloride to elute theproduct (3%). MS=516 (Na+)

EXAMPLE 91

[0321]

[0322] To a DMSO(3 mL) solution of Compound 44 (0.123 g, 0.343 mmol),was added 2-propyl bromide (0.04 mL, 0.411 mmol), followed by dropwiseaddition of KOt-Bu (0.41 mL, 0.411 mmol, 1 M in THF). The reactionmixture was stirred at RT for 20 hr, poured into water (15 mL) andextracted with EtOAc (3×15 mL). The combined organics were washed withwater, then brine and dried over Na₂SO₄. The filtrate was concentratedin vacuo to give a mixture of starting material and the desired productas a yellow oil. These two compounds were separated by preparativereverse-phase HPLC to give Compound 101 (2%). MS=440 (K+)

EXAMPLE 92

[0323]

[0324] Melylate Formation:

[0325] To a suspension of Compound 65 (0.0521 g, 0.129 mmol) in DMF (5mL) was added triethylamine (0.04 mL, 0.3 mmol) followed bymethanesulfonyl chloride (0.01 mL, 0.2 mmol). The reaction was stirredat RT for 2 hr. At this time, the reaction was poured into water (20 mL)and extracted with EtOAc (3×20 mL). The combined organics were washedwith water, then brine and dried over MgSO₄. The filtrate wasconcentrated in vacuo to give a gold residue. The mesylate was used inthe next reaction without further purification.

[0326] Phthalimide Formation:

[0327] To a DMF (10 mL) solution of the above compound (0.060 g, 0.12mmol) was added potassium phthalimide (0.046 g, 0.25 mmol) and thereaction was heated to 60° C. After heating for 20 hr the solution wascooled to RT and poured into water (40 mL), extracted with EtOAc (3×20mL), and the organics were washed with water and brine. After dryingover MgSO₄, the organics were concentrated to an orange solid, thenpurified by silica gel column chromatography. The desired phthalimidewas eluted from the column with 5% methanol/methylene chloride in 14%yield.

[0328] Amine Formation:

[0329] To a methanol solution containing the phthalimide compound fromabove (0.0095 g, 0.018 mmol) was added hydrazine monohydrate (0.010 mL,0.036 mmol) and the reaction mixture was heated to reflux for 10 hr. Themethanol was removed in vacuo and the reaction was dissolved in EtOAc(10 mL), washed with water, and then brine. The organics were then driedover MgSO₄, and the filtrate was concentrated to a gold film. Theresidue was triturated with 5% methanol/ethyl acetate to removeimpurities and provide the product as a pale yellow film (20%). MS=403(M+H), 425 (Na+)

EXAMPLE 93

[0330]

[0331] Formation of the Thiomorpholine Compound:

[0332] To a solution of Compound 93 (0.147 g, 0.353 mmol) in DMF (5 mL)at 60° C. was added thiomorpholine (0.18 mL, 1.76 mmol) and the reactionwas heated to 85° C. for five hours. After cooling to RT, water (15 mL)was added and an off-white precipitate formed which was collected byvacuum filtration and discarded. The filtrate was extracted with EtOAc(3×40 mL) and the extracts were washed repeatedly with water to removeresidual DMF. The organic portion was dried over Na₂SO₄ and the filtratewas concentrated in vacuo to a yellow film. The sulfide was isolated in30% yield and used without further purification.

[0333] Formation of the Sulfone:

[0334] The compound from above (0.053 g, 0.03 mmol) was taken up inmethylene chloride (5 mL) and m-CPBA (77% peroxide) (0.069 g, 0.31 mmol)was added to the solution at RT. After 3 hr the reaction was quenchedwith aqueous NaHCO₃, and a white precipitate formed. The solid wascollected by vacuum filtration and dried to recover the sulfone (7%).MS=573 (Na+)

EXAMPLE 94

[0335]

[0336] To Compound 93 (0.130 g, 0.313 mmol) in DMF (7 mL) was addedCs₂CO₃ (0.510 g, 1.56 mmol) followed by ethanethiol (0.03 mL, 0.4 mmol)at RT and 10 the reaction was stirred for 3 hr. The reaction mixture wasdiluted with water and the aqueous portion was extracted with EtOAc(3×20 mL). The combined organics were dried over MgSO₄ and the filtratewas concentrated to give a white film. The crude product was purifiedusing silica gel column chromatography, eluting the pure product (23%)with 5% methanol/ethyl acetate.

[0337] Formation of the Sulfoxide:

[0338] The sulfide from above (0.0162 g, 0.0340 mmol) was dissolved inmethylene chloride (2 mL) and (Polystyrylmethyl) trimethylammoniummetaperiodate (0.0283 g, 2.40 mmol/g) (Novabiochem®) was added. Thereaction was stirred gently for 20 hr at RT. The resin was removed byfiltration, and washed with methylene chloride. The filtrate wasconcentrated in vacuo to give a crude mixture of products. The sulfoxidewas purified by silica gel column chromatography, eluting with 10%methanol/EtOAc. The resulting product was a diastereomeric mixture ofsulfoxides. MS=494 (M+H), 516 (Na+)

EXAMPLE 95

[0339]

[0340] A suspension of Compound 65 (0.4468 g, 1.11 mmols) in THF (2 mL)was cooled to −78° C. and LDA (0.72 mL, 2.0 M in THF) was addeddropwise. After 15 min, tetrabenzylpyrophosphate (0.7753 g, 1.44 mmol)was added and the mixture was stirred for 30 min at −78° C. The reactionmixture was allowed to warm to RT and was then stirred for 24 hr. Thecrude product was chromatographed on silica and the product (40%) elutedwith 2% methanol/methylene chloride. MS=664 (M+H), 686 (Na+)

EXAMPLE 96

[0341]

[0342] To the crude mesylate from Example 92 (0.087 g, 0.181 mmol) inDMF (10 mL) was added thiomorpholine (0.055 mL, 0.543 mmol) and thereaction was heated to 80° C. for 20 hr. Upon cooling the reactionmixture was poured into water and extracted with EtOAc (3×40 mL). Thecombined organics were washed with water, brine, and then dried overMgSO₄. The mixture was filtered and concentrated in vacuo to give a goldoil. The oil was purified using silica gel column chromatography elutingwith 10% methanol/ethyl acetate gave Compound 106 in 9% yield. MS=489(M+H), 511 (Na+)

EXAMPLE 97

[0343]

[0344] To a DMF (20 mL) solution of Compound 44 (0.4126 g, 1.148 mmols),at 37° C. was added KOt-Bu (2.3 mL, 1.0 M in THF) and the reactionmixture was stirred for 20 min. To this mixture was added chloromethylmethyl sulfide (0.15 mL, 1.7 mmols) and the reaction was stirred for 20hr. The reaction mixture was poured into water and a precipitate formed.The solid was collected by vacuum filtration and dried for several hoursunder vacuum at 50° C. The two regioisomers were separated bypreparative reverse-phase HPLC to give Compound 107 in a 6% yield andCompound 108 in a 12% yield. MS=420 (M+H), 442 (Na+)

EXAMPLE 98

[0345]

[0346] To Compound 108 (0.0540 g, 0.1289 mmol) in methylene chloride (5mL) was added tetrabutylammonium oxone (0.3517 g, 0.3866 mmol). Thesolution was stirred at RT for 20 hr. The reaction mixture was dilutedwith methylene chloride and washed with water. The organic solution wasdried over Na₂SO₄, filtered and concentrated to a yellow solid. Silicagel column chromatography was used to purify the product with 3%methanol/methylene chloride as the eluent. The Compound 109 wasisolated, after trituration with EtOAc, as a white solid in 12% yield.MS=452 (M+H), 474 (Na+)

EXAMPLE 99

[0347]

[0348] To a suspension of Compound 65 (0.1185 g, 0.294 mmol) in DMF (5mL) was added triethylamine (0.090 mL, 0.65 mmol) followed bymethanesulfonyl chloride (0.03 mL, 0.4 mmol). After stirring at RT for30 min sodium thiomethoxide (0.0247 g, 0.352 mmol) was added directly tothe reaction mixture which was heated to 50° C. for 3 hours. The mixturewas poured into water (20 mL) and extracted with EtOAc (3×10 mL). Thecombined organics were washed with water, then brine and dried overNa₂SO₄. The filtrate was concentrated in vacuo to afford an orange oilin approximately 38% yield, which was used without further purificationin the next reaction. MS=434 (M+H), 456 (Na+)

EXAMPLE 100

[0349]

[0350] The crude oil from Example 99 (0.0982 g, 0.226 mmol) wasdissolved in methylene chloride (10 mL) and tetrabutylammonium oxone(0.2321 g, 0.680 mmol) was added. The reaction mixture was stirred at RTfor 5 hr and then diluted with methylene chloride. The organic portionwas washed with water several times, and dried over Na₂SO₄. The organicsolution was concentrated to a yellow solid and purified by silica gelcolumn chromatography. The product was eluted with 3% methanol/methylenechloride to provide the product in 2% yield. MS=466 (M+H), 488 (Na+)

EXAMPLE 101

[0351]

[0352] A methylene chloride (15 mL) solution of Compound 108 (0.0758 g,0.181 mmol) was cooled to −78° C. before adding m-CPBA (0.0405 g, 0.181mmol) as a methylene chloride solution, dropwise, over 20 min. Thereaction mixture was stirred for another 30 min at −78° C. then warmedto room temperature. The mixture was washed with aqueous sodiumbicarbonate, brine, and then dried over sodium sulfate. The filtrate wasconcentrated in vacuo to a yellow solid, and then purified by HPLC togive the separate diastereomeric sulfoxide products of undeterminedstereochemistry, 12% overall yield. MS=436 (M+H), 458 (Na+)

EXAMPLE 102

[0353]

[0354] Di-t-butyl N,N-diethylphosphoramidite (0.13 mL, 0.45 mmol) wasadded dropwise to a stirred suspension of Compound 65 (0.1134 g, 0.281mmol) in THF and 1H-tetrazole (0.1969 g, 2.81 mmol) at RT undernitrogen. The reaction was stirred at RT for 2.5 hr. After cooling thereaction mixture to −78° C. m-CPBA (0.0631 g, 0.281 mmol) was added inseveral portions. The mixture was stirred for 1 hr at −78° C., thenwarmed to RT for another hour.

[0355] The reaction mixture was diluted with EtOAc and washedsuccessively with 10% aqueous sodium bisulfite, saturated aqueousNaHCO₃, and water. The combined organics were dried over MgSO₄,filtered, and concentrated to a tan oil. The crude oil waschromatographed on silica and Compound 114 was eluted with 5%methanol/EtOAc and concentrated to provide a pale yellow film (7%).MS=596 (M+H), 618 (Na+)

EXAMPLE 103

[0356]

[0357] Benzyl Chloride Formation:

[0358] To Compound 65 (0.0594 g, 0.147 mmol) suspended in a 2:1 solutionof methylene chloride/acetonitrile was added triethylamine (0.10 mL,0.74 mmol), followed by (4-chloromethyl) benzoyl chloride (0.035 g, 0.18mmol). The reaction mixture was stirred at RT for 3 hr. The solvent wasremoved and water was added to precipitate a yellow solid. The solid wascollected by filtration and dried to a pale yellow powder. The productwas used without further purification.

[0359] Final Product:

[0360] To a mixture of the benzyl chloride, described above, (0.040 g,0.074 mmol) in DMF (5 mL) was added Nal (0.005 g) and morpholine (0.050mL, 0.56 mmol) at 50° C. for 20 hr. The reaction mixture was poured intowater, and extracted with methylene chloride (3×15 mL) and the combinedorganics were washed with water, then brine, and dried over MgSO₄. Theorganic layer was filtered and concentrated in vacuo to a yellow solid.Compound 115 was purified by silica gel column chromatography and elutedwith 5% methanol/methylene chloride as a white film (27%). MS=607 (M+H)

EXAMPLE 104

[0361]

[0362] To a mixture of the benzyl chloride (prepared as in Example 103)(0.1280 g, 0.230 mmol) in DMF (10 mL) was added Nal (0.005 g) anddimethylamine (0.92 mL, 2.0 M in MeOH,), at 50° C. for 1 hr. Methanolwas removed in vacuo, and the reaction mixture was diluted withmethylene chloride before being washed with water and brine. Thecombined organics were dried over MgSO₄, and concentrated in vacuo to ayellow waxy solid. The crude product was purified by silica gel columnchromatography eluting with 2% methanol/methylene chloride. Furtherpurification was achieved by preparative reverse phase HPLC to provideCompound 116 as a white powder (3%). MS=565 (M+H)

EXAMPLE 105

[0363]

[0364] To a mixture of the benzyl chloride (as prepared in Example 103)(0.1330 g, 0.239 mmol) in DMF (10 mL) was added Nal (0.010 g) andN-methyl piperdine (0.13 mL, 1.2 mmol) at 50° C. for 2 hr. The reactionmixture was poured into water and extracted with EtOAc (3×15 mL). Thecombined organics were washed with water, brine, and dried over MgSO₄.The organic layer was filtered and concentrated in vacuo to a yellowfilm. Compound 117 was purified by silica gel column chromatography andeluted with 10% methanol/methylene chloride as a yellow film (2%). MS620 (M+H)

EXAMPLE 106

[0365]

[0366] A slurry of DCC (0.5033 g, 0.496 mmol), N,N-dimethylglycine(0.1020 g, 0.992 mmol), and DMAP (0.0606 g, 0.496 mmol) in methylenechloride was stirred for 5 min at RT before adding Compound 65. Thereaction mixture was stirred at RT for 24 h, diluted with methylenechloride and washed with water. The organics were dried over MgSO₄ andconcentrated to a yellow oil. The oil was triturated with EtOAc to givea white solid which was collected by filtration. The filtrate wasconcentrated to a yellow oil, and purified by silica gel columnchromatography, eluting with 2% methanol/methylene chloride (2%). MS=489(M+H), 511 (Na+)

EXAMPLE 107

[0367]

[0368] A mixture of EDCl (0.950 g, 4.96 mmol), DMAP (0.121 g, 0.992mmol) and carbobenzyloxy-L-valine was stirred for 15 min at RT in 20 mLmethylene chloride. Compound 65 (0.400 g, 0.992 mmol) was added and thereaction mixture was stirred at RT for several hours. The mixture wasdiluted with water and extracted with methylene chloride (3×30 mL). Thecombined extracts were washed with water, brine, and then dried overNa₂SO₄. The crude product was concentrated to a yellow oil, and purifiedby silica gel column chromatography using 3% methanol/methylenechloride. A yellow foam was recovered as the product (43%). MS 637(M+H), 659 (Na+)

EXAMPLE 108

[0369]

[0370] A solution of Compound 119 (0.134 g, 0.210 mmol) in MeOH (5 mL),THF (2.5 mL) and water (1 mL) was added to 0.67 mL of 0.5 N aqueous HCland 0.014 g 10% Pd on C. The mixture was shaken under an initialpressure of 50 psi H₂ at RT for 18 hr. At this time, the reactionmixture was filtered through Celite, eluting the product with methanol.The filtrates were concentrated in vacuo to give an off-white foam. Thisproduct was purified by preparative reverse-phase HPLC using 0.1% AcOHas an additive. The diacetate salt was isolated as a white powder (0.060g, 43%). MS=503 (M+H), 525 (Na+)

EXAMPLE 109

[0371]

[0372] To a solution of Compound 114 in CH₂Cl₂ is added TFA. Thereaction mixture is stirred for 30 min and the solvent is removed on arotavap. The product is isolated by triturating with ether to give asolid. (M+H)=484

[0373] The invention has been described in detail with particularreference to the above embodiments thereof. The above embodiments andexamples are given to illustrate the scope and spirit of the presentinvention. These embodiments and examples will make apparent, to thoseskilled in the art, other embodiments and examples. These otherembodiments and examples are within the contemplation of the presentinvention. It will be understood that variations and modifications canbe effected within the spirit and scope of the invention; therefore, theinstant invention should be limited only by the appended claims.

We claim:
 1. A compound of Formula I

wherein: R is selected from the group consisting of OH, O-Aryl,O-Heteroaryl, N₃, OR′, OSO₂R″, —NR′″R″″, or

 wherein: (i) R′ is straight-chain or branched acyl having up to 6carbon atoms or benzyl; (ii) R″ is straight-chain or branched alkyl,having up to 5 carbon atoms, phenyl or tolyl; and (iii) R′″ and R″″ areindependently selected from the group consisting of H, cycloalkyl having3 to 6 carbon atoms, phenyl or tert-butoxycarbonyl,fluorenyloxycarbonyl, benzyloxycarbonyl, straight-chain or branchedalkyl having up to 6 carbon atoms which is optionally substituted bycyano or alkoxycarbonyl having up to 4 carbon atoms, —CO₂—R₁, —CO—R₁,—CS—R₁, and —SO₂—R₄, in which R₁ is selected from the group consistingof H, cycloalkyl having 3 to 6 carbon atoms, trifluoromethyl or phenyl,benzyl or acyl having up to 5 carbon atoms, straight-chain or branchedalkyl having up to 6 carbon atoms, said alkyl optionally substituted bystraight-chain or branched alkoxycarbonyl having up to 5 carbon atoms,OH, cyano, up to 3 halogen atoms, and —NR₅ R₆ in which R₅ and R₆ areidentical or different and are selected from H, phenyl or straight-chainor branched alkyl having up to 4 carbon atoms; R₄ is selected fromstraight-chain or branched alkyl having up to 4 carbon atoms or phenyland; R_(4a) is CN, COR_(4c), COOR_(4c) CONHR_(4c), CO—NR_(4c), R_(4d),SO₂R_(4c), or NO₂; R_(4b) is H, alkyl, OR_(4c), SR_(4c), amino,NHR_(4c), NR_(4c), R_(4d); R_(4c) and R_(4d) are independently selectedfrom H, alkyl, aryl, or in the case of any NR_(4c)R_(4d) group R_(4c)and R_(4d) taken together with the nitrogen atom to which they areattached form a unsubstituted or substituted pyrrolidinyl, piperidinylor morpholinyl group; X is 0 to 4 members independently selected fromthe group consisting of halogen, OH, nitro, C₁₋₈ alkoxy, C₁₋₈alkyl-amino, di(C₁₋₈-alkyl-)amino, carboxy, alkoxycarbonyl, C₁₋₈alkyl-CO—O—, C₁₋₈ alkyl-CO—NH—, carboxamide, CN, amine, C₃₋₆ cycloalkyl,C₁₋₈ alkyl optionally substituted with one or more members selected fromthe group consisting of F, Cl, OH; and Y is a radical of Formulae II orIII:

 wherein R₅, R₆, R₇, and R₈ are each independently H, alkyl, CN, nitro,C₁₋₈ alkyl, halo-C₁₋₈-alkyl, formyl, carboxy, alkoxycarbonyl,carboxamide, or R₅ and R₆ and/or R₇ and R₈ together form an oxo group;R₉, and R₁₀ are each independently H, halogen, alkyl, OH, CN, nitro,C₁₋₈ alkyl, halo-C₁₋₈-alkyl, C₁₋₈ alkoxyl, amino, C₁₋₈-alkyl-amino,di(C₁₋₈-alkyl-amino, formyl, carboxy, alkoxycarbonyl, C₁₋₈-alkyl-CO—O—,C₁₋₈-alkyl-CO—NH—, carboxamide, or amine;

 is a fused phenyl ring or a five- or six-membered heteroaromatic ringhaving one to four members selected from the group consisting of S, O,and N; Z is halogen, alkyl, substituted-alkyl, aryl, substituted-aryl,heteroaryl, substituted-heteroaryl, CN, CHO, COalkyl, amino, alkoxy,HNCO—(C₁-C₈alkyl), allyl, propargyl, allenyl, or N-alkylthiocarbamoyl;and m is 0 or 1, and the pharmaceutically acceptable salts and estersthereof.
 2. The compound of claim 1 wherein Y is selected from the groupconsisting of


3. The compound of claim 1 wherein R is selected from the groupconsisting of


4. A compound of claim 1 wherein Z is propargyl, allyl, allenyl,N-alkylthiocarbamoyl, heteroaryl, substituted-heteroaryl, alkyl, or asubstituted alkyl having one or more substituents selected form thegroup consisting of amino, dialkylamino, cycloalkyl, hydroxy, oxo,alkoxycarbonyl, benzyloxy, arylthio, alkylthio, hydroxyalkylthio,alkylsulfinyl, alkylsulfonyl, carboxy, phosphonooxy,dialkylphosphonooxy, dibenzylphosphonooxy, cyano, halo, trialkylsilyl,dialkylphenylsilyl, aryl, heteroaryl, heterocyclo,heterocyclomethylbenzoyloxy, dialkylaminomethylbenzoyloxy,dialkylaminoalkylcarbonyloxy, benzyloxycarbonylaminoalkylcarbonyloxy,and aminoalkylcarbonyloxy.
 5. The compound of claim 4 wherein Z isselected from the group consisting of propargyl, allyl, allenyl,N-alkylthiocarbamoyl, ethyl, isopropyl, t-butyl, 2-hydroxyethyl,3-hydroxypropyl, 2,2,2-trifluoroethyl, cyanomethyl, 2-cyanoethyl,cyclopropylmethyl, 2-oxopropyl, methylthiomethyl, 2-methylthioethyl,methylsulfonymethyl, 2-methylsulfonylethyl, methylsulifinyl methyl,t-butoxycarbonylmethyl, 2-carboxyethyl, 2-(di-t-butylphosphonooxy)ethyl,2-(dibenzylphosphonooxy)ethyl, 2-phosphonooxyethyl, 2-aminoethyl,2-(diethylamino)ethyl, 2-(dimethylamino)ethyl, 2-(4-morpholinyl)ethyl,2-(4-thiomorpholinyl)ethyl, trimethylsilylmethyl,dimethylphenylsilylmethyl, benzyloxymethyl, benzyl, 5-tetrazolylmethyl,3-pyridylmethyl, 2-pyridylmethyl, 2-oxiranylmethyl,2-oxooxazolidin-5-ylmethyl, 2,3-dihydroxypropyl,2-hydroxy-3-(1-piperidinyl)propyl, 2-hydroxy-3-(4-morpholinyl)propyl,2-hydroxy-3-phenylthiopropyl, 2-hydroxy-3-ethylthiopropyl,2-hydroxy-3-(2-hydroxyethylthio)propyl,3-[4-(1,1-dioxothiomorpholinyl)]-2-hydroxypropyl,3-ethylsulfinyl-2-hydroxypropyl,2-[4-(4-morpholinylmethyl)benzoyloxy]ethyl,2-[4-(dimethylaminomethyl)benzoyloxy]ethyl,2-[4-(4-methyl-1-piperazinylmethyl)benzoyloxy]ethyl,2-(dimethylaminoacetoxy)ethyl,2-[2-(benzyloxycarbonylamino)-3-methylbutyryloxy]ethyl,2-(2-amino-3-methylbutyryloxy)ethyl, 2-pyridinyl, pyridazinyl, and2-pyrimidinyl.
 6. A compound of claim 1 having the formula:


7. A compound of claim 1 having the formula:


8. A compound of claim 1 having the formula:


9. A compound of claim 1 having the formula:


10. A compound of claim 1 having the formula:


11. A compound of claim 1 having the formula:


12. A compound of claim 1 having the formula:


13. A compound of claim 1 having the formula:


14. A compound of claim 1 having the formula:


15. A compound of claim 1 having the formula:


16. A compound of claim 1 having the formula:


17. A compound of claim 1 having the formula:


18. A compound of claim 1 having the formula:


19. A compound of claim 1 having the formula:


20. A compound of claim 1 having the formula:


21. A compound of claim 1 having the formula:


22. A compound of claim 1 having the formula:


23. A compound of claim 1 having the formula:


24. A compound of claim 1 having the formula:


25. A compound of claim 1 having the formula:


26. A compound of claim 1 having the formula:


27. A compound of claim 1 having the formula:


28. A compound of claim 1 having the formula:


29. A compound of claim 1 having the formula:


30. A compound of claim 1 having the formula:


31. A compound of claim 1 having the formula:


32. A compound of claim 1 having the formula:


33. A compound of claim 1 having the formula:


34. A compound of claim 1 having the formula:


35. A compound of claim 1 having the formula:


36. A compound of claim 1 having the formula:


37. A compound of claim 1 having the formula:


38. A compound of claim 1 having the formula:


39. A compound of claim 1 having the formula:


40. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically acceptable carrier.
 41. A method oftreating a subject having a condition caused by or contributed to bybacterial infection, which comprises administering to said mammal atherapeutically effective amount of the compound according to claim 1.42. A method of preventing a subject from suffering from a conditioncaused by or contributed to by bacterial infection, which comprisesadministering to the subject a prophylactically effective dose of thepharmaceutical composition of a compound according to claim
 1. 43. Themethod of claim 41 wherein said condition is selected from the groupconsisting of community-acquired pneumonia, upper and lower respiratorytract infections, skin and soft tissue infections, bone and jointinfections and hospital-acquired lung infections.
 44. The method ofclaim 42 wherein said condition is selected from the group consisting ofcommunity-acquired pneumonia, upper and lower respiratory tractinfections, skin and soft tissue infections, bone and joint infectionsand hospital-acquired lung infections.
 45. The method of claim 41wherein said bacterium is selected from the group consisting of S.aureus, S. epidermidis, S. pneumoniae, S. pyogenes, Enterococcus spp.,Moraxella catarrhalis and H. influenzae.
 46. The method of claim 42wherein said bacterium is selected from the group consisting of S.aureus, S. epidermidis, S. pneumoniae, S. pyogenes, Enterococcus spp.,Moraxella catarrhalis and H. influenzae.
 47. The method of claim 41wherein said bacterium is a Gram-positive coccus.
 48. The method ofclaim 42 wherein said bacterium is a Gram-positive coccus.
 49. Themethod of claim 47 wherein said Gram-positive coccus is drug-resistant.50. The method of claim 48 wherein said Gram-positive coccus isdrug-resistant.